Genes

14 pages, 258 KB

Open AccessEditor’s ChoiceReview

Cutting-Edge Advances in Cystic Fibrosis: From Gene Therapy to Personalized Medicine and Holistic Management

by Giuseppe Fabio Parisi, Vito Terlizzi, Sara Manti, Maria Papale, Giulia Pecora, Santiago Presti, Monica Tosto and Salvatore Leonardi

Genes 2025, 16(4), 402; https://doi.org/10.3390/genes16040402 - 30 Mar 2025

Cited by 4 | Viewed by 5632

Abstract

Cystic fibrosis (CF), a genetic disorder characterized by mutations in the CFTR gene, has seen significant advances in treatment through cutting-edge approaches such as gene therapy and personalized medicine. This review examines the current and emerging strategies shaping CF care, focusing on novel [...] Read more.

Cystic fibrosis (CF), a genetic disorder characterized by mutations in the CFTR gene, has seen significant advances in treatment through cutting-edge approaches such as gene therapy and personalized medicine. This review examines the current and emerging strategies shaping CF care, focusing on novel therapies that target the root cause of CF and optimize patient outcomes. CFTR modulators have transformed cystic fibrosis management by enhancing protein function for specific mutations, leading to improved lung function and quality of life. Concurrently, gene therapy offers transformative potential by aiming to correct CFTR mutations using tools like CRISPR/Cas9 or prime editing, though challenges remain in delivery and long-term efficacy. The integration of precision medicine, facilitated by genomic and computational technologies, allows for personalized treatment plans that account for genetic variability and disease severity. Complementing these approaches, holistic management emphasizes the importance of psychological support and nutritional optimization, acknowledging CF’s multi-system impact. Future directions include exploring anti-inflammatory agents and microbiome modulation to further mitigate disease morbidity. However, global disparities in treatment access continue to challenge equitable healthcare delivery, underscoring the need for policy reform and international cooperation. By synthesizing these developments, this review highlights the transformative potential of modern CF treatments, advocating for continued innovation and global healthcare equity, with the ultimate goal of dramatically improving life expectancy and quality of life for individuals with CF. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

26 pages, 1157 KB

Open AccessEditor’s ChoiceReview

Pharmacogenomic and Pharmacomicrobiomic Aspects of Drugs of Abuse

by Alejandro Borrego-Ruiz and Juan J. Borrego

Genes 2025, 16(4), 403; https://doi.org/10.3390/genes16040403 - 30 Mar 2025

Cited by 6 | Viewed by 2632

Abstract

Background/Objectives: This review examines the role of pharmacogenomics in individual responses to the pharmacotherapy of various drugs of abuse, including alcohol, cocaine, and opioids, to identify genetic variants that contribute to variability in substance use disorder treatment outcomes. In addition, it explores the [...] Read more.

Background/Objectives: This review examines the role of pharmacogenomics in individual responses to the pharmacotherapy of various drugs of abuse, including alcohol, cocaine, and opioids, to identify genetic variants that contribute to variability in substance use disorder treatment outcomes. In addition, it explores the pharmacomicrobiomic aspects of substance use, highlighting the impact of the gut microbiome on bioavailability, drug metabolism, pharmacodynamics, and pharmacokinetics. Results: Research on pharmacogenetics has identified several promising genetic variants that may contribute to the individual variability in responses to existing pharmacotherapies for substance addiction. However, the interpretation of these findings remains limited. It is estimated that genetic factors may account for 20–95% of the variability in individual drug responses. Therefore, genetic factors alone cannot fully explain the differences in drug responses, and factors such as gut microbiome diversity may also play a significant role. Drug microbial biotransformation is produced by microbial exoenzymes that convert low molecular weight organic compounds into analogous compounds by oxidation, reduction, hydrolysis, condensation, isomerization, unsaturation, or by the introduction of heteroatoms. Despite significant advances in pharmacomicrobiomics, challenges persist including the lack of standardized methodologies, inter-individual variability, limited understanding of drug biotransformation mechanisms, and the need for large-scale validation studies to develop microbiota-based biomarkers for clinical use. Conclusions: Progress in the pharmacogenomics of substance use disorders has provided biological insights into the pharmacological needs associated with common genetic variants in drug-metabolizing enzymes. The gut microbiome and its metabolites play a pivotal role in various stages of drug addiction including seeking, reward, and biotransformation. Therefore, integrating pharmacogenomics with pharmacomicrobiomics will form a crucial foundation for significant advances in precision and personalized medicine. Full article

(This article belongs to the Section Pharmacogenetics)

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11 pages, 1286 KB

Open AccessEditor’s ChoiceReview

Toxoplasma Gondii Replication During Belatacept Treatment in Kidney Transplantation: A Case Report and a Review of the Literature

by Raffaella Vigilante, Raafiah Izhar, Rossella Di Paola, Ananya De, Rosa Maria Pollastro, Giovanna Capolongo, Giulio Viceconte and Mariadelina Simeoni

Genes 2025, 16(4), 391; https://doi.org/10.3390/genes16040391 - 29 Mar 2025

Cited by 3 | Viewed by 1465

Abstract

Belatacept is a chimeric protein that acts as a selective blocker of T-lymphocyte co-stimulation. It has been proposed for the prevention of kidney transplant rejection. This paper reports a literature review on pharmacological characteristics of belatacept and genetic factors influencing its efficacy and [...] Read more.

Belatacept is a chimeric protein that acts as a selective blocker of T-lymphocyte co-stimulation. It has been proposed for the prevention of kidney transplant rejection. This paper reports a literature review on pharmacological characteristics of belatacept and genetic factors influencing its efficacy and safety profile. A severe case of neurotoxoplasmosis observed in a kidney transplant recipient (KTR) treated with belatacept is also described. It appears that the interference of belatacept on guanylate binding proteins (GBPs) expression in antigen-presenting cells (APC) cytoplasm could be involved in Toxoplasma gondii (Toxo-g) reactivation in seropositive KTRs. Additionally, genetic variations in immune regulatory genes encoding CTLA-4 and Blimp-1 may influence individual susceptibility to infection and immune modulation under belatacept therapy. In conclusion, we highlight the importance of drug avoidance and/or increased surveillance in Toxo-g IgG-positive KTR. We also retain that further studies on the host defense pathways involved in the surveillance of opportunistic pathogens in KTR are strongly desirable. Full article

(This article belongs to the Special Issue From Genetic to Molecular Basis of Kidney Diseases)

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26 pages, 2297 KB

Open AccessEditor’s ChoiceReview

Cardiac Fibroblasts: Helping or Hurting

by Mohammad Shameem, Shelby L. Olson, Ezequiel Marron Fernandez de Velasco, Akhilesh Kumar and Bhairab N. Singh

Genes 2025, 16(4), 381; https://doi.org/10.3390/genes16040381 - 27 Mar 2025

Cited by 3 | Viewed by 5126

Abstract

Cardiac fibroblasts (CFs) are the essential cell type for heart morphogenesis and homeostasis. In addition to maintaining the structural integrity of the heart tissue, muscle fibroblasts are involved in complex signaling cascades that regulate cardiomyocyte proliferation, migration, and maturation. While CFs serve as [...] Read more.

Cardiac fibroblasts (CFs) are the essential cell type for heart morphogenesis and homeostasis. In addition to maintaining the structural integrity of the heart tissue, muscle fibroblasts are involved in complex signaling cascades that regulate cardiomyocyte proliferation, migration, and maturation. While CFs serve as the primary source of extracellular matrix proteins (ECM), tissue repair, and paracrine signaling, they are also responsible for adverse pathological changes associated with cardiovascular disease. Following activation, fibroblasts produce excessive ECM components that ultimately lead to fibrosis and cardiac dysfunction. Decades of research have led to a much deeper understanding of the role of CFs in cardiogenesis. Recent studies using the single-cell genomic approach have focused on advancing the role of CFs in cellular interactions, and the mechanistic implications involved during cardiovascular development and disease. Arguably, the unique role of fibroblasts in development, tissue repair, and disease progression categorizes them into the friend or foe category. This brief review summarizes the current understanding of cardiac fibroblast biology and discusses the key findings in the context of development and pathophysiological conditions. Full article

(This article belongs to the Special Issue Genomics and Genetics of Cardiovascular Diseases)

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12 pages, 1551 KB

Open AccessEditor’s ChoiceArticle

Cross-Kingdom Communication via Plant-Derived Extracellular Vesicle Nucleic Acids in Genetically Engineered Nicotiana tabacum

by Lorena Urbanelli, Federica Delo, Giada Cerrotti, Emidio Albertini, Jacopo Lucci, Sandra Buratta, Eleonora Calzoni, Stefano Giovagnoli, Luana Lugini, Cristina Federici, Federica Fratini, Valentino Mercati and Carla Emiliani

Genes 2025, 16(3), 356; https://doi.org/10.3390/genes16030356 - 20 Mar 2025

Cited by 3 | Viewed by 2066

Abstract

Background/Objectives: Plants release extracellularly lipid bilayer-enclosed vesicles of nanometric size that can be retrieved in their fluids. Plant-derived extracellular vesicles (PDEVs) have mostly been involved in modulating host–pathogen interaction, making them a tool for cross-kingdom communication with a key role in plant immunity. [...] Read more.

Background/Objectives: Plants release extracellularly lipid bilayer-enclosed vesicles of nanometric size that can be retrieved in their fluids. Plant-derived extracellular vesicles (PDEVs) have mostly been involved in modulating host–pathogen interaction, making them a tool for cross-kingdom communication with a key role in plant immunity. In addition, PDEVs have demonstrated promising therapeutic features, not only in terms of intrinsic nutraceutical properties but also of active molecules’ delivery. Transgenic plants have been developed for a variety of purposes, i.e., to improve their functional properties like crops, but also to produce therapeutic molecules. However, it is unclear whether transgenes can end up in PDEVs, thus making them a vehicle for their cross-kingdom diffusion into the environment. Methods: Here, we investigated the association of transgenic DNA and RNA with PDEVs secreted by tobacco (Nicotiana tabacum) engineered to express the neomycine phosphotransferase II (Npt-II) gene. PDEVs were isolated from leaf apoplastic fluid by ultracentrifugation and characterized for their morphology and size. The association of DNA and RNA was assessed by qRT-PCR and their immunomodulatory properties by assaying PDEVs-induced IL1β and IL10 on THP1 monocytes. Results: Npt-II RNA, but not DNA, could be amplified from PDEVs, whereas no differences were observed between wt and transgenic tobacco PDEVs in terms of immunomodulatory properties. Conclusions: Although a different behaviour by other types of RNAs or DNAs could still be possible, our findings indicate that in this model, PDEVs are not associated with transgenic DNA, but they can protect RNA, including transgenic RNA, from degradation, contributing to their cross-kingdom spreading. Full article

(This article belongs to the Section Plant Genetics and Genomics)

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16 pages, 1019 KB

Open AccessEditor’s ChoiceArticle

Relationship Between Vitamin D Receptor Gene BsmI Polymorphism and 25-Hydroxyvitamin D Total Levels in Slovak Postmenopausal Women with Reduced Bone Mineral Density

by Marta Mydlárová Blaščáková, Zuzana Lőrinczová, Lenka Anderková, Olga Czerwińska-Ledwig, Ľudmila Mikulová, Hedviga Hrušovská, Bernadeta Jędrzejkiewicz and Anna Piotrowska

Genes 2025, 16(3), 337; https://doi.org/10.3390/genes16030337 - 13 Mar 2025

Cited by 2 | Viewed by 1557

Abstract

Objectives: The BsmI polymorphism of the VDR gene (vitamin D receptor) is one of the important genetic variants influencing the development of osteoporosis. Measurement and evaluation of the 25-hydroxyvitamin D (25(OH)D) concentration in individuals with reduced bone mineral density are essential because deficiency [...] Read more.

Objectives: The BsmI polymorphism of the VDR gene (vitamin D receptor) is one of the important genetic variants influencing the development of osteoporosis. Measurement and evaluation of the 25-hydroxyvitamin D (25(OH)D) concentration in individuals with reduced bone mineral density are essential because deficiency of this hormone causes impaired bone mineralization, leads to low BMD (bone mineral density), and influences fracture formation. The aim of the study was to investigate the relationship between the VDR gene BsmI polymorphism and 25(OH)D levels in Slovak postmenopausal women. Materials and Methods: The study population consisted of 287 untreated postmenopausal women, who were divided into three groups based on T-scores: normal (CG = 65), osteopenia (OPE = 126), and osteoporosis (OPO = 96). DNA isolation was performed using a standard protocol. Genetic analyses of the BsmI (rs1544410) polymorphism of the VDR gene were performed using the TaqMan SNP genotyping assays. Biochemical analysis of total 25(OH)D was performed in blood serum using the electrochemiluminescence method. Results: The chi-square test confirmed that the mutant T allele was not associated with the development of osteoporosis (p = 0.419). Through Kruskal–Wallis analysis, we found significant differences (p < 0.05, p < 0.01) in total 25(OH)D concentrations in individual genotypes of the BsmI variant of the VDR gene between the groups of women studied. Conclusions: It can be concluded that the VDR gene and its variant BsmI as well as 25(OH)D total may be relevant markers in the etiology of the search for individuals at risk of osteoporosis. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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23 pages, 10624 KB

Open AccessEditor’s ChoiceReview

Curious Dichotomies of Apolipoprotein E Function in Alzheimer’s Disease and Cancer—One Explanatory Mechanism of Inverse Disease Associations?

by Claire M. Perks, Rachel M. Barker, Mai Alhadrami, Omar Alkahtani, Emily Gill, Mary Grishaw, Abigail J. Harland, Peter Henley, Haonan Li, Ellie O’Sullivan, Gideon Stone, Xiaoyu Su and Patrick G. Kehoe

Genes 2025, 16(3), 331; https://doi.org/10.3390/genes16030331 - 12 Mar 2025

Cited by 3 | Viewed by 3810

Abstract

An apparent “inverse” relationship exists between two seemingly unconnected conditions, Alzheimer’s disease (AD) and cancer, despite sharing similar risk factors, like increased age and obesity. AD is associated with amyloid beta (A

β

) plaques and neurofibrillary tau tangles that cause neural degeneration; [...] Read more.

An apparent “inverse” relationship exists between two seemingly unconnected conditions, Alzheimer’s disease (AD) and cancer, despite sharing similar risk factors, like increased age and obesity. AD is associated with amyloid beta (A

β

) plaques and neurofibrillary tau tangles that cause neural degeneration; cancer, in contrast, is characterized by enhanced cell survival and proliferation. Apolipoprotein E (ApoE) is the main lipoprotein found in the central nervous system and via its high affinity with lipoprotein receptors plays a critical role in cholesterol transport and uptake. ApoE has 3 protein isoforms, ApoE E2, ApoE E3, and ApoE E4, respectively encoded for by 3 allelic variants of APOE (

ε

2,

ε

3, and

ε

4). This review examines the characteristics and function of ApoE described in both AD and cancer to assimilate evidence for its potential contribution to mechanisms that may underly the reported inverse association between the two conditions. Of the genetic risk factors relevant to most cases of AD, the most well-known with the strongest contribution to risk is APOE, specifically the

ε

4 variant, whereas for cancer risk, APOE has not featured as a significant genetic contributor to risk. However, at the protein level in both conditions, ApoE contributes to disease pathology via affecting lipid physiology and transport. In AD, A

β

-dependent and -independent interactions have been suggested, whereas in cancer, ApoE plays a role in immunoregulation. Understanding the mechanism of action of ApoE in these diametrically opposed diseases may enable differential targeting of therapeutics to provide a beneficial outcome for both. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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42 pages, 3151 KB

Open AccessEditor’s ChoiceReview

Methods for Extracellular Vesicle Isolation: Relevance for Encapsulated miRNAs in Disease Diagnosis and Treatment

by Maria Ljungström and Elisa Oltra

Genes 2025, 16(3), 330; https://doi.org/10.3390/genes16030330 - 12 Mar 2025

Cited by 8 | Viewed by 4837

Abstract

Extracellular vesicles (EVs) are nanovesicles that facilitate intercellular communication by carrying essential biomolecules under physiological and pathological conditions including microRNAs (miRNAs). They are found in various body fluids, such as blood, urine, and saliva, and their levels fluctuate with disease progression, making them [...] Read more.

Extracellular vesicles (EVs) are nanovesicles that facilitate intercellular communication by carrying essential biomolecules under physiological and pathological conditions including microRNAs (miRNAs). They are found in various body fluids, such as blood, urine, and saliva, and their levels fluctuate with disease progression, making them valuable diagnostic tools. However, isolating EVs is challenging due to their small size and biological complexity. Here, we summarize the principles behind the most common EV isolation methods including ultracentrifugation, precipitation, immunoaffinity, sorting, ultrafiltration, size exclusion chromatography, and microfluidics while highlighting protocol strengths and weaknesses. We also review the main strategies to identify and quantify circulating miRNAs with a particular focus on EV-encapsulated miRNAs. Since these miRNAs hold special clinical interest derived from their superior stability and therapeutic potential, the information provided here should provide valuable guidance for future research initiatives in the promising field of disease diagnostic and treatment based on EV-encapsulated miRNAs. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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19 pages, 9223 KB

Open AccessEditor’s ChoiceArticle

Genomic Patterns of Homozygosity and Genetic Diversity in the Rhenish German Draught Horse

by Johanna Sievers and Ottmar Distl

Genes 2025, 16(3), 327; https://doi.org/10.3390/genes16030327 - 11 Mar 2025

Cited by 3 | Viewed by 1176

Abstract

Background/Objectives: The Rhenish German draught horse is an endangered German horse breed, originally used as working horse in agriculture. Therefore, the objective of this study was to evaluate the breed’s genetic diversity using pedigree and genomic data in order to analyze classical and [...] Read more.

Background/Objectives: The Rhenish German draught horse is an endangered German horse breed, originally used as working horse in agriculture. Therefore, the objective of this study was to evaluate the breed’s genetic diversity using pedigree and genomic data in order to analyze classical and ancestral pedigree-based inbreeding, runs of homozygosity, ROH islands, and consensus ROH. Methods: We studied the genome-wide genotype data of 675 Rhenish German draught horses and collated pedigree-based inbreeding coefficients for these horses. The final dataset contained 64,737 autosomal SNPs. Results: The average number of ROH per individual was 43.17 ± 9.459 with an average ROH length of 5.087 Mb ± 1.03 Mb. The average genomic inbreeding coefficient F_ROH was 0.099 ± 0.03, the pedigree-based classical inbreeding coefficient F_PED 0.016 ± 0.021, and ancestral inbreeding coefficients ranged from 0.03 (F_{a_Kal}) to 0.51 (Ahc). Most ROH (55.85%) were classified into the length category of 2–4 Mb, and the minority (0.43%) into the length category of >32 Mb. The effective population size (N_e) decreased in the last seven generations (~65 years) from 189.43 to 58.55. Consensus ROH shared by 45% of the horses were located on equine chromosomes 3 and 7, while ROH islands exceeding the 99th percentile threshold were identified on chromosomes 2, 3, 5, 7, 9, 10, and 11. These ROH islands contained genes associated with morphological development (HOXB cluster), fertility (AURKC, NLRP5, and DLX3), muscle growth, and skin physiology (ZNF gene cluster). Conclusions: This study highlights how important it is to monitor genetic diversity in endangered populations with genomic data. The results of this study will help to develop breeding strategies to ensure the conservation of the German Rhenish draught horse population and show whether favorable alleles from the overrepresented candidate genes within ROH were transmitted to the next generation. Full article

(This article belongs to the Special Issue The Whole-Genome Analysis and Breed Evolution of Horses)

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16 pages, 1316 KB

Open AccessEditor’s ChoiceArticle

Targeting Optimal Bone Regions: Correlations Between Bone Density and DNA Quality in Small Skeletal Elements

by Živa Miriam Geršak, Vladka Salapura, Eva Podovšovnik and Irena Zupanič-Pajnič

Genes 2025, 16(3), 291; https://doi.org/10.3390/genes16030291 - 27 Feb 2025

Cited by 2 | Viewed by 1074

Abstract

Background: Identifying the optimal bone regions for DNA analysis is critical, as DNA preservation and quality vary significantly across bone types and structures and is defined as intra-bone variability. This study aimed to evaluate the correlation between computed tomography (CT)-measured bone density [...] Read more.

Background: Identifying the optimal bone regions for DNA analysis is critical, as DNA preservation and quality vary significantly across bone types and structures and is defined as intra-bone variability. This study aimed to evaluate the correlation between computed tomography (CT)-measured bone density and DNA preservation in small skeletal elements to identify optimal regions for DNA analysis. Methods: 137 bones from six skeletal elements excavated from a single burial site were analysed using Dual-Source CT (DSCT) to map compact and cancellous regions. DNA was extracted using a demineralisation method and quantified via real-time PCR to assess DNA quantity and degradation. Results: Among 461 bone regions analysed (137 bones; patellae, calcaneus, talus, the navicular bones, the cuboid bone, and the medial cuneiform bone), a significant difference in DNA quantity was observed only in the calcaneus, where the sulcus contained more DNA than the body. No significant differences in the degradation index were detected among bone segments or skeletal elements. Correlations between CT-measured bone density and DNA quantity or degradation index were region-specific. Higher bone density correlated positively with DNA quantity in compact regions of the calcaneus and talus. Regarding degradation, a positive correlation (higher bone density → higher degradation) was observed in the patella’s anterior surface, while a negative correlation (higher bone density → lower degradation) was found in the talus’s sulcus, the opposite side of the talar sulcus, the posterior calcaneal articular facet, and the cuboid’s tuberosity. No significant correlations were found in other bone segments. Conclusions: Our study identified small skeletal elements, particularly the patella and the navicular bone, as promising sources for DNA analysis. While bone density correlated with DNA preservation in some cases, the relationship was inconsistent. Our findings support the use of small bones in forensic and archaeological research and warrant further investigation. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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10 pages, 242 KB

Open AccessEditor’s ChoiceReview

Genetics of Gallstones

by Agnieszka Pęczuła, Adam Czaplicki and Adam Przybyłkowski

Genes 2025, 16(3), 256; https://doi.org/10.3390/genes16030256 - 22 Feb 2025

Cited by 2 | Viewed by 4614

Abstract

Gallstone disease (GSD) is a common gastrointestinal disorder affecting approximately 10–20% of the global adult population, characterized by the presence of gallstones, predominantly cholesterol-based, in the gallbladder and/or biliary ducts. While many patients remain asymptomatic, more than 20% develop clinical symptoms such as [...] Read more.

Gallstone disease (GSD) is a common gastrointestinal disorder affecting approximately 10–20% of the global adult population, characterized by the presence of gallstones, predominantly cholesterol-based, in the gallbladder and/or biliary ducts. While many patients remain asymptomatic, more than 20% develop clinical symptoms such as abdominal pain, nausea, vomiting, jaundice, and anorexia, potentially leading to severe complications like acute cholecystitis and biliary pancreatitis. GSD has a significant genetic predisposition, with the variable prevalence of the disease according to ethnicity being highest in American and European countries and lowest in Asian and African populations. Numerous genes encoding membrane transporters involved in bile metabolism are associated with GSD, including in particular members of ATP-binding cassette transporters and others, which affect bile lithogenicity and contribute to the development of gallstones. Specific mutations in these genes are linked to an increased risk of gallstone formation, especially in individuals with certain hereditary conditions such as hemolytic diseases, thyroid disorders, and hyperparathyroidism. Advances in genetic studies have identified new variants that influence the risk of cholelithiasis, although the exact mechanisms remain partially understood in many cases. This review briefly summarizes the genetic causes of cholelithiasis, highlighting various pathogenetic mechanisms. It presents the currently used treatments and the potential implications of widely applied genetic diagnostics. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

22 pages, 1816 KB

Open AccessEditor’s ChoiceArticle

The Association Between Statin Drugs and Rhabdomyolysis: An Analysis of FDA Adverse Event Reporting System (FAERS) Data and Transcriptomic Profiles

by Robert Morris, Kun Bu, Weiru Han, Savanah Wood, Paola M. Hernandez Velez, Jacob Ward, Ariana Crescitelli, Madison Martin and Feng Cheng

Genes 2025, 16(3), 248; https://doi.org/10.3390/genes16030248 - 21 Feb 2025

Cited by 6 | Viewed by 10858

Abstract

Background/Objectives: Rhabdomyolysis, a dangerous breakdown of skeletal muscle, has been reported as an adverse event in those prescribed a statin therapy for the treatment of hypercholesterolemia. Statin drugs are some of the most prescribed treatments for elevated cholesterol levels. The purpose of this [...] Read more.

Background/Objectives: Rhabdomyolysis, a dangerous breakdown of skeletal muscle, has been reported as an adverse event in those prescribed a statin therapy for the treatment of hypercholesterolemia. Statin drugs are some of the most prescribed treatments for elevated cholesterol levels. The purpose of this comparative study was to determine the association between the statin drugs used and the risk of rhabdomyolysis using the FDA Adverse Event Reporting System (FAERS) and transcriptomic data. Methods: A disproportionality analysis was performed to compare the risk of rhabdomyolysis between the reference statin drug (simvastatin) and the treatment group, with patient age assessed as a possible confounder. In addition, association rule mining was utilized to both identify other adverse events that frequently presented with rhabdomyolysis and identify possible drug-drug interactions (DDIs). Finally, public transcriptomic data were explored to identify the possible genetic underpinnings highlighting these differences in rhabdomyolysis risk across statins. Results: Rhabdomyolysis is a commonly reported adverse event for patients treated with statins, particularly those prescribed simvastatin. Simvastatin was associated with a more than 2-fold increased likelihood of rhabdomyolysis compared to other statins. Men were twice as likely to report rhabdomyolysis than women regardless of statin treatment, with the highest risk observed for pravastatin (ROR = 2.30, p < 0.001) and atorvastatin (ROR = 2.03, p < 0.0001). Several possible DDIs were identified, including furosemide/Lasix, allopurinol clopidogrel/Plavix, and pantoprazole, which may elevate rhabdomyolysis risk through impaired muscle function and delayed statin metabolism. Finally, nine myopathic genes were identified as possible regulators of statin-induced rhabdomyolysis, including DYSF, DES, PLEC, CAPN3, SCN4A, TNNT1, SDHA, MYH7, and PYGM in primary human muscle cells. Conclusions: Simvastatin was associated with the highest risk of rhabdomyolysis. The risk of rhabdomyolysis was more pronounced in men than women. Several possible DDIs were identified including furosemide/Lasix, allopurinol clopidogrel/Plavix, and pantoprazole. Full article

(This article belongs to the Section Toxicogenomics)

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21 pages, 4387 KB

Open AccessEditor’s ChoiceArticle

Exploring the Genotoxic Stress Response in Primed Orphan Legume Seeds Challenged with Heat Stress

by Andrea Pagano, Conrado Dueñas, Jr., Nicolò Bedotto, Amine Elleuch, Bassem Khemakhem, Hanen El Abed, Eleni Tani, Maria Goufa, Dimosthenis Chachalis and Alma Balestrazzi

Genes 2025, 16(2), 235; https://doi.org/10.3390/genes16020235 - 19 Feb 2025

Cited by 3 | Viewed by 1250

Abstract

Background/Objectives: The increased frequency of extreme weather events related to climate change, including the occurrence of extreme temperatures, severely affects crop yields, impairing global food security. Heat stress resulting from temperatures above 30 °C is associated with poor germination performance and stand establishment. [...] Read more.

Background/Objectives: The increased frequency of extreme weather events related to climate change, including the occurrence of extreme temperatures, severely affects crop yields, impairing global food security. Heat stress resulting from temperatures above 30 °C is associated with poor germination performance and stand establishment. The combination of climate-resilient crop genotypes and tailored seed priming treatments might represent a reliable strategy to overcome such drawbacks. This work explores the potential of hydropriming as a tool to mitigate the heat-stress-mediated impact on germination performance in orphan legumes. Methods: For each tested species (Lathyrus sativus L., Pisum sativum var. arvense and Trigonella foenum-graecum L.), two accessions were investigated. Germination tests were performed at 25 °C, 30 °C, 35 °C and 40 °C to assess the heat stress tolerance threshold. Hydropriming was then applied and germination tests were performed at 40 °C to test the impact of the treatment on the seeds’ ability to cope with heat stress. An alkaline comet assay and Quantitative Real Time-Polymerase Chain Reaction were performed on embryos excised from primed and control seeds. Results: Phenotyping at the germination and seedling development stage highlighted the accession-specific beneficial impact of hydropriming under heat stress conditions. In L. sativus seeds, the alkaline comet assay revealed the dynamics of heat stress-induced DNA damage accumulation, as well as the repair patterns promoted by hydropriming. The expression patterns of genes involved in DNA repair and antioxidant response were consistently responsive to the hydropriming and heat wave conditions in L. sativus accessions. Full article

(This article belongs to the Special Issue DNA Damage Repair and Plant Stress Response)

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31 pages, 3433 KB

Open AccessEditor’s ChoiceReview

Nucleotide Excision Repair: Insights into Canonical and Emerging Functions of the Transcription/DNA Repair Factor TFIIH

by Amélie Zachayus, Jules Loup-Forest, Vincent Cura and Arnaud Poterszman

Genes 2025, 16(2), 231; https://doi.org/10.3390/genes16020231 - 19 Feb 2025

Cited by 6 | Viewed by 4763

Abstract

Nucleotide excision repair (NER) is a universal cut-and-paste DNA repair mechanism that corrects bulky DNA lesions such as those caused by UV radiation, environmental mutagens, and some chemotherapy drugs. In this review, we focus on the human transcription/DNA repair factor TFIIH, a key [...] Read more.

Nucleotide excision repair (NER) is a universal cut-and-paste DNA repair mechanism that corrects bulky DNA lesions such as those caused by UV radiation, environmental mutagens, and some chemotherapy drugs. In this review, we focus on the human transcription/DNA repair factor TFIIH, a key player of the NER pathway in eukaryotes. This 10-subunit multiprotein complex notably verifies the presence of a lesion and opens the DNA around the damage via its XPB and XPD subunits, two proteins identified in patients suffering from Xeroderma Pigmentosum syndrome. Isolated as a class II gene transcription factor in the late 1980s, TFIIH is a prototypic molecular machine that plays an essential role in both DNA repair and transcription initiation and harbors a DNA helicase, a DNA translocase, and kinase activity. More recently, TFIIH subunits have been identified as participating in other cellular processes, including chromosome segregation during mitosis, maintenance of mitochondrial DNA integrity, and telomere replication. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Microorganisms, Plants and Mammalian Systems)

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18 pages, 2370 KB

Open AccessEditor’s ChoiceReview

Chromatin Remodulator CHD4: A Potential Target for Cancer Interception

by Krishnendu Goswami, Karthikkumar Venkatachalam, Surya P. Singh, Chinthalapally V. Rao and Venkateshwar Madka

Genes 2025, 16(2), 225; https://doi.org/10.3390/genes16020225 - 15 Feb 2025

Cited by 2 | Viewed by 3269

Abstract

Cancer initiation and progression are associated with numerous somatic mutations, genomic rearrangements, and structure variants. The transformation of a normal cell into a cancer cell involves spatio-temporal changes in the regulation of different gene networks. The accessibility of these genes within the cell [...] Read more.

Cancer initiation and progression are associated with numerous somatic mutations, genomic rearrangements, and structure variants. The transformation of a normal cell into a cancer cell involves spatio-temporal changes in the regulation of different gene networks. The accessibility of these genes within the cell nucleus is manipulated via nucleosome remodeling ATPases, comprising one of the important mechanisms. Here, we reviewed studies of an ATP-dependent chromatin remodulator, chromodomain helicase DNA-binding 4 (CHD4), in cancer. Multiple domains of CHD4 are known to take part in nucleosome mobilization and histone binding. By binding with other proteins, CHD4 plays a vital role in transcriptional reprogramming and functions as a key component of Nucleosome Remodeling and Deacetylase, or NuRD, complexes. Here, we revisit data that demonstrate the role of CHD4 in cancer progression, tumor cell proliferation, DNA damage responses, and immune modulation. Conclusively, CHD4-mediated chromatin accessibility is essential for transcriptional reprogramming, which in turn is associated with tumor cell proliferation and cancer development. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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17 pages, 3232 KB

Open AccessEditor’s ChoiceArticle

Retinal Disease Variability in Female Carriers of RPGR Variants Associated with Retinitis Pigmentosa: Clinical and Genetic Parameters

by Sena A. Gocuk, Thomas L. Edwards, Jasleen K. Jolly, Fred K. Chen, David C. Sousa, Myra B. McGuinness, Terri L. McLaren, Tina M. Lamey, Jennifer A. Thompson and Lauren N. Ayton

Genes 2025, 16(2), 221; https://doi.org/10.3390/genes16020221 - 13 Feb 2025

Cited by 3 | Viewed by 2601

Abstract

Objectives: We sought to investigate the visual function, retinal features, and genotype–phenotype correlations of an Australian cohort of RPGR carriers. Methods: In this cross-sectional study, we evaluated RPGR carriers seen in Melbourne and Perth between 2013 and 2023 and healthy women seen between [...] Read more.

Objectives: We sought to investigate the visual function, retinal features, and genotype–phenotype correlations of an Australian cohort of RPGR carriers. Methods: In this cross-sectional study, we evaluated RPGR carriers seen in Melbourne and Perth between 2013 and 2023 and healthy women seen between 2022 and 2023 in Melbourne. Visual acuity tests, fundus-tracked microperimetry, and retinal imaging were performed. RPGR carriers were classified into four retinal phenotypes (normal, radial, focal pigmentary retinopathy, and male pattern phenotype) and compared against healthy controls. Genotype–phenotype relationships in the RPGR carriers were investigated. Results: Thirty-five female RPGR carriers and thirty healthy controls were included in this study. The median ages were 40 and 48.5 years for RPGR carriers and controls, respectively (p = 0.26). Most RPGR carriers (89%) had a genetic diagnosis. Best-corrected visual acuity (BCVA), low luminance visual acuity, retinal sensitivity, central inner retinal thickness (IRT, 1°), and photoreceptor complex (PRC) thickness across the central 1–7° of the retina differed between phenotypes of RPGR carriers. On average, RPGR carriers with ORF15 variants (n = 25 carriers) had reduced LLVA, a greater IRT at 1°, and thinner PRC thickness at 7° from the fovea (all p < 0.05) compared to those with exon 1–14 variants. Conclusions: Female RPGR carriers with severe retinal phenotypes had significantly decreased visual function and changes in retinal structure in comparison to both the controls and carriers with mild retinal disease. BCVA, LLVA, retinal sensitivity, and retinal thickness are biomarkers for detecting retinal disease in RPGR carriers. The genetic variant alone did not influence retinal phenotype; however, RPGR carriers with ORF15 variants exhibited reduced retinal and visual measurements compared to those with exon 1–14 variants. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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67 pages, 32566 KB

Open AccessEditor’s ChoiceArticle

Advances in Understanding the Karyotype Evolution of Tetrapulmonata and Two Other Arachnid Taxa, Ricinulei and Solifugae

by Jiří Král, Alexandr Sember, Klára Divišová, Tereza Kořínková, Azucena C. Reyes Lerma, Ivalú M. Ávila Herrera, Martin Forman, František Šťáhlavský, Jana Musilová, Sabrina Torres Kalme, José G. Palacios Vargas, Magda Zrzavá, Iva Vrbová, Jairo A. Moreno-González, Paula E. Cushing, Alexander V. Gromov, Štěpánka Šebestiánová, Vendula Bohlen Šlechtová, Lorenzo Prendini and Tharina L. Bird

Genes 2025, 16(2), 207; https://doi.org/10.3390/genes16020207 - 8 Feb 2025

Cited by 2 | Viewed by 2961

Abstract

Background/Objectives: Arachnids are a megadiverse arthropod group. The present study investigated the chromosomes of pedipalpid tetrapulmonates (orders Amblypygi, Thelyphonida, Schizomida) and two arachnid orders of uncertain phylogenetic placement, Ricinulei and Solifugae, to reconstruct their karyotype evolution. Except for amblypygids, the cytogenetics of these [...] Read more.

Background/Objectives: Arachnids are a megadiverse arthropod group. The present study investigated the chromosomes of pedipalpid tetrapulmonates (orders Amblypygi, Thelyphonida, Schizomida) and two arachnid orders of uncertain phylogenetic placement, Ricinulei and Solifugae, to reconstruct their karyotype evolution. Except for amblypygids, the cytogenetics of these arachnid orders was almost unknown prior to the present study. Methods: Chromosomes were investigated using methods of standard (Giemsa-stained preparations, banding techniques) and molecular cytogenetics (fluorescence in situ hybridization, comparative genomic hybridization). Results and Conclusions: New data for 38 species, combined with previously published data, suggest that ancestral arachnids possessed low to moderate 2n (22–40), monocentric chromosomes, one nucleolus organizer region (NOR), low levels of heterochromatin and recombinations, and no or homomorphic sex chromosomes. Karyotypes of Pedipalpi and Solifugae diversified via centric fusions, pericentric inversions, and changes in the pattern of NORs and, in solifuges, also through tandem fusions. Some solifuges display an enormous amount of constitutive heterochromatin and high NOR number. It is hypothesized that the common ancestor of amblypygids, thelyphonids, and spiders exhibited a homomorphic XY system, and that telomeric heterochromatin and NORs were involved in the evolution of amblypygid sex chromosomes. The new findings support the Cephalosomata clade (acariforms, palpigrades, and solifuges). Hypotheses concerning the origin of acariform holocentric chromosomes are presented. Unlike current phylogenetic hypotheses, the results suggest a sister relationship between Schizomida and a clade comprising other tetrapulmonates as well as a polyploidization in the common ancestor of the clade comprising Araneae, Amblypygi, and Thelyphonida. Full article

(This article belongs to the Special Issue Commemorating the Launch of the Section "Cytogenomics")

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13 pages, 1313 KB

Open AccessEditor’s ChoiceArticle

Product Speculation from Carotenogenic Gene Cluster of Nonlabens spongiae Genome, and Identification of Myxol and Functional Analysis of Each Gene

by Keisuke Nakazawa, Daiki Mineo, Takuya Harayama, Susumu Yoshizawa, Shinichi Takaichi and Kenjiro Sugiyama

Genes 2025, 16(2), 202; https://doi.org/10.3390/genes16020202 - 7 Feb 2025

Cited by 2 | Viewed by 1397

Abstract

Background: Myxol, a monocyclic carotenoid with β- and ψ-end groups, has been identified in only a limited number of bacteria, such as flavobacteria and cyanobacteria. Despite its biological significance, the biosynthetic pathway of myxol is not well understood, and studies on its physiological [...] Read more.

Background: Myxol, a monocyclic carotenoid with β- and ψ-end groups, has been identified in only a limited number of bacteria, such as flavobacteria and cyanobacteria. Despite its biological significance, the biosynthetic pathway of myxol is not well understood, and studies on its physiological functions and biological activities are limited because of its rarity. Methods: BLAST homology searches for carotenoid biosynthesis genes in the genome of Nonlabens were performed. The carotenogenesis-related genes in the genome of the marine flavobacteria Nonlabens spongiae were individually cloned and functionally characterized using a heterologous Escherichia coli expression system. Carotenoids from N. spongiae were identified using an LC-MS analysis. Results: We identified a gene cluster involved in carotenoid biosynthesis in the genome of N. spongiae. This cluster includes genes encoding phytoene synthase (CrtB), phytoene desaturase (CrtI), lycopene cyclase (CrtY), carotenoid 1,2-hydratase (CruF), carotenoid 3,4-desaturase (ψ-end group) (CrtD), carotenoid 2-hydroxylase (ψ-end group) (CrtA-OH), and carotene hydro-xylase (CrtZ). Based on the characteristics of these enzymes, the primary products were predicted to be myxol and/or zeaxanthin. A spectroscopic analysis confirmed that myxol was the primary carotenoid. Furthermore, a plasmid containing a reconstructed gene cluster and geranylgeranyl pyrophosphate synthase (CrtE) located outside the cluster was introduced into E. coli. This system predominantly accumulated myxol, indicating that the reconstructed gene cluster enabled efficient myxol production in E. coli. Conclusions: This study highlighted the potential biotechnological applications of the carotenoid biosynthesis gene clusters for myxol production. Full article

(This article belongs to the Section Microbial Genetics and Genomics)

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13 pages, 1346 KB

Open AccessEditor’s ChoiceArticle

The POLG Variant c.678G>C; p.(Gln226His) Is Associated with Mitochondrial Abnormalities in Fibroblasts Derived from a Patient Compared to a First-Degree Relative

by Imra Mantey, Felix Langerscheidt, Çağla Çakmak Durmaz, Naomi Baba, Katharina Burghardt, Mert Karakaya and Hans Zempel

Genes 2025, 16(2), 198; https://doi.org/10.3390/genes16020198 - 5 Feb 2025

Cited by 1 | Viewed by 1645

Abstract

Background: The nuclear-encoded enzyme polymerase gamma (Pol-γ) is crucial in the replication of the mitochondrial genome (mtDNA), which in turn is vital for mitochondria and hence numerous metabolic processes and energy production in eukaryotic cells. Variants in the POLG gene, which encodes the [...] Read more.

Background: The nuclear-encoded enzyme polymerase gamma (Pol-γ) is crucial in the replication of the mitochondrial genome (mtDNA), which in turn is vital for mitochondria and hence numerous metabolic processes and energy production in eukaryotic cells. Variants in the POLG gene, which encodes the catalytic subunit of Pol-γ, can significantly impair Pol-γ enzyme function. Pol-γ-associated disorders are referred to as POLG-spectrum disorders (POLG-SDs) and are mainly autosomal-recessively inherited. Clinical manifestations include muscle weakness and fatigue, and severe forms of the disease can lead to premature death in infancy, childhood, and early adulthood, often associated with seizures, liver failure, or intractable epilepsy. Here, we analyzed fibroblasts from a compound heterozygous patient with the established pathogenic variant c.2419C>T; p.(Arg807Cys) and a previously undescribed variant c.678G>C; p.(Gln226His) with a clinical manifestation compatible with POLG-SDs, sensory ataxic neuropathy, and infantile muscular atrophy. We conducted a battery of functional studies for Pol-γ and mitochondrial dysfunction on the patient’s fibroblasts, to test whether the novel variant c.678G>C; p.(Gln226His) may be causative in human disease. Aims/Methods: We analyzed skin-derived fibroblasts in comparison to a first-degree relative (the mother of the patient), an asymptomatic carrier harboring only the established c.2419C>T; p.(Arg807Cys) mutation. Assessments of mitochondrial function included measurements of mtDNA content, mRNA levels of mitochondrial genes, mitochondrial mass, and mitochondrial morphology. Case Presentation and Results: A 13-year-old male presented with symptoms starting at three years of age, including muscle weakness and atrophy in the lower extremities and facial muscles, which later extended to the upper limbs, voice, and back muscles, without further progression. The patient also reported fatigue and muscle pain after physical activity, with no sensory deficits. Extensive diagnostic tests such as electromyography, nerve conduction studies, muscle biopsy, and MRI were unremarkable. Exome sequencing revealed that he carried the compound heterozygous variants in POLG c.678G>C; p.(Gln226His) and c.2419C>T; p.(Arg807Cys), but no other potential genetic pathogenic causes. In comparison to a first-degree relative (his mother) who only carried the c.2419C>T; p.(Arg807Cys) pathogenic mutation, in vitro analyses revealed a significant reduction in mtDNA content (~50%) and mRNA levels of mtDNA-encoded proteins. Mitochondrial mass was reduced by approximately 20%, and mitochondrial interconnectivity within cells was impaired, as determined by fluorescence microscopy and mitochondrial staining. Conclusions: Our findings suggest that the c.678G>C; p.(Gln226His) variant, in conjunction with the c.2419C>T; p.(Arg807Cys) mutation, may compromise mtDNA replication and mitochondrial function and could result in clinically significant mitochondriopathy. As this study is based on one patient compared to a first-degree relative (but with an identical mitochondrial genome), the pathogenicity of c.678G>C; p.(Gln226His) of POLG should be confirmed in future studies, in particular, in conjunction with other POLG-variants. Full article

(This article belongs to the Special Issue Molecular Genetics of Neurodegenerative Diseases and Neuromuscular Diseases)

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40 pages, 4205 KB

Open AccessEditor’s ChoiceArticle

Evaluation of Prenatal Transportation Stress on DNA Methylation (DNAm) and Gene Expression in the Hypothalamic–Pituitary–Adrenal (HPA) Axis Tissues of Mature Brahman Cows

by Audrey L. Earnhardt-San, Emilie C. Baker, Kubra Z. Cilkiz, Rodolfo C. Cardoso, Noushin Ghaffari, Charles R. Long, Penny K. Riggs, Ronald D. Randel, David G. Riley and Thomas H. Welsh, Jr.

Genes 2025, 16(2), 191; https://doi.org/10.3390/genes16020191 - 4 Feb 2025

Cited by 1 | Viewed by 1273

Abstract

Background/Objectives: The experience of prenatal stress results in various physiological disorders due to an alteration of an offspring’s methylome and transcriptome. The objective of this study was to determine whether PNS affects DNA methylation (DNAm) and gene expression in the stress axis tissues [...] Read more.

Background/Objectives: The experience of prenatal stress results in various physiological disorders due to an alteration of an offspring’s methylome and transcriptome. The objective of this study was to determine whether PNS affects DNA methylation (DNAm) and gene expression in the stress axis tissues of mature Brahman cows. Methods: Samples were collected from the paraventricular nucleus (PVN), anterior pituitary (PIT), and adrenal cortex (AC) of 5-year-old Brahman cows that were prenatally exposed to either transportation stress (PNS, n = 6) or were not transported (Control, n = 8). The isolated DNA and RNA samples were, respectively, used for methylation and RNA-Seq analyses. A gene ontology and KEGG pathway enrichment analysis of each data set within each sample tissue was conducted with the DAVID Functional Annotation Tool. Results: The DNAm analysis revealed 3, 64, and 99 hypomethylated and 2, 93, and 90 hypermethylated CpG sites (FDR < 0.15) within the PVN, PIT, and AC, respectively. The RNA-Seq analysis revealed 6, 25, and 5 differentially expressed genes (FDR < 0.15) in the PVN, PIT, and AC, respectively, that were up-regulated in the PNS group relative to the Control group, as well as 24 genes in the PIT that were down-regulated. Based on the enrichment analysis, several developmental and cellular processes, such as maintenance of the actin cytoskeleton, cell motility, signal transduction, neurodevelopment, and synaptic function, were potentially modulated. Conclusions: The methylome and transcriptome were altered in the stress axis tissues of mature cows that had been exposed to prenatal transportation stress. These findings are relevant to understanding how prenatal experiences may affect postnatal neurological functions. Full article

(This article belongs to the Section Animal Genetics and Genomics)

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22 pages, 1500 KB

Open AccessEditor’s ChoiceArticle

Molecular Review of Suspected Alport Syndrome Patients—A Single-Centre Experience

by Paulina Halat-Wolska, Elżbieta Ciara, Michał Pac, Łukasz Obrycki, Dorota Wicher, Katarzyna Iwanicka-Pronicka, Ewelina Bielska, Beata Chałupczyńska, Dorota Siestrzykowska, Grażyna Kostrzewa, Piotr Stawiński, Rafał Płoski, Mieczysław Litwin and Krystyna Chrzanowska

Genes 2025, 16(2), 196; https://doi.org/10.3390/genes16020196 - 4 Feb 2025

Cited by 2 | Viewed by 2781

Abstract

Background: Alport syndrome (AS) is a clinically and genetically heterogeneous glomerulopathy resulting from pathogenic variants in COL4A3, COL4A4, and COL4A5. Genetic diagnosis is increasingly being conducted using next-generation sequencing (NGS). Methods: Within eight years, we examined a group of 247 Polish individuals [...] Read more.

Background: Alport syndrome (AS) is a clinically and genetically heterogeneous glomerulopathy resulting from pathogenic variants in COL4A3, COL4A4, and COL4A5. Genetic diagnosis is increasingly being conducted using next-generation sequencing (NGS). Methods: Within eight years, we examined a group of 247 Polish individuals and found in total 138 unrelated probands suspected with AS based on clinical course, laboratory findings, and/or family history, as well as the total of 109 family members. We applied a targeted NGS panel to identify the genetic spectrum of AS. Known and novel variants were revealed, and detailed evaluation was performed according to ACMG/AMP guidelines to classify them as pathogenic/likely pathogenic/VUS changes. Identified genotypes were compared with clinical manifestations: hematuria, proteinuria, chronic kidney disease, sensorineural hearing impairment, ocular abnormalities, and hypertension. Results: The molecular background was established in 109/138 probands. Overall, 79 different COL4A3-COL4A5 changes (56 known and 23 novel) were revealed. About 97% were SNVs, and only two COL4A5 CNVs were identified. In total, 11 recurrent COL4A3-COL4A5 variants were observed, including the most frequent COL4A5:p.Gly624Asp, accounting for 31% of X-linked AS. Conclusions: The use of NGS panel has shown considerable promise in the field of AS, increasing diagnostic rate to 79% and reducing time to diagnosis. The phenotype-driven gene panel, specific for genetic diseases in the pediatric population, is an affordable alternative to WGS and WES, offering comparable diagnostic efficacy and supporting its implementation as a first-line genetic test in rare diseases, including AS. Based on the obtained genotype–phenotype correlation, we assessed that NGS allows us to avoid invasive renal biopsy in AS diagnosis. It provides AS confirmation/exclusion, atypical AS identification, symptomatic/asymptomatic monoallelic COL4A3-COL4A5 carrier (especially COL4A5 females) determination, and inheritance pattern establishment. AS diagnosis confirmation enables clinical course prediction and is crucial for the early introduction of renoprotective treatment with renin–angiotensin–aldosterone system blockade, aimed at slowing the disease progression and estimating the risk in family members, which is important for genetic counselling. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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13 pages, 535 KB

Open AccessEditor’s ChoiceReview

Narrative Review of Genetic and Immunological Mechanisms Involved in the Pathogenesis of Kimura’s Disease: New Therapeutic Targets

by Antonella Loperfido, Carlo Cavaliere, Bruno Fionda, Gianluca Bellocchi, Simonetta Masieri and Marco Caminati

Genes 2025, 16(2), 194; https://doi.org/10.3390/genes16020194 - 4 Feb 2025

Cited by 2 | Viewed by 1883

Abstract

Kimura’s disease (KD) is a rare, chronic inflammatory disorder that predominantly affects young men of East Asian descent. It is characterized by painless solid masses primarily localized to the deep subcutaneous tissues of the head and neck, eosinophilia, and elevated serum immunoglobulin E [...] Read more.

Kimura’s disease (KD) is a rare, chronic inflammatory disorder that predominantly affects young men of East Asian descent. It is characterized by painless solid masses primarily localized to the deep subcutaneous tissues of the head and neck, eosinophilia, and elevated serum immunoglobulin E (IgE). While the exact cause remains unclear, the pathogenesis is thought to involve dysregulated immune responses, particularly those mediated by T-helper cells 2 (Th2), eosinophils, and IgE production. Advances in molecular biology have suggested that genetic factors play a significant role in the development and progression of this chronic inflammatory condition. Recent studies have implicated several genes and immune pathways in its development, and understanding these genetic components may provide insights into better diagnostic tools and therapeutic strategies for KD. In this regard, biological therapies, by targeting the immune mechanisms underlying KD, have been used to treat this challenging condition with promising results, contributing to a better understanding of the pathogenesis of this rare disorder. The aim of this study was to review the literature concerning the genetic factors and immune mechanisms that contribute to the pathogenesis of KD, with a special focus on the role of biological therapies. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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18 pages, 878 KB

Open AccessEditor’s ChoiceReview

Integrating Machine Learning-Based Approaches into the Design of ASO Therapies

by Jamie Leckie and Toshifumi Yokota

Genes 2025, 16(2), 185; https://doi.org/10.3390/genes16020185 - 2 Feb 2025

Cited by 3 | Viewed by 4936

Abstract

Rare diseases impose a significant burden on affected individuals, caregivers, and healthcare systems worldwide. Developing effective therapeutics for these small patient populations presents substantial challenges. Antisense oligonucleotides (ASOs) have emerged as a promising therapeutic approach that targets the underlying genetic cause of disease [...] Read more.

Rare diseases impose a significant burden on affected individuals, caregivers, and healthcare systems worldwide. Developing effective therapeutics for these small patient populations presents substantial challenges. Antisense oligonucleotides (ASOs) have emerged as a promising therapeutic approach that targets the underlying genetic cause of disease at the RNA level. Several ASOs have gained FDA approval for the treatment of genetic conditions, including use in personalized N-of-1 trials. However, despite their potential, ASOs often exhibit limited clinical efficacy, and optimizing their design is a complex process influenced by numerous factors. Machine learning-based platforms, including eSkip-Finder and ASOptimizer, have been developed to address these challenges by predicting optimal ASO sequences and chemical modifications to enhance efficacy. eSkip-Finder focuses on exon-skipping applications, while ASOptimizer aims to optimize ASOs for RNA degradation. Preliminary in vitro results have demonstrated the promising predictive power of these platforms. However, limitations remain, including their generalizability to alternative targets and gaps in their consideration of all factors influencing ASO efficacy and safety. Continued advancements in machine learning models, alongside efforts to incorporate additional features affecting ASO efficacy and safety, hold significant promise for the field. These platforms have the potential to streamline ASO development, reduce associated costs, and improve clinical outcomes, positioning machine learning as a key tool in the future of ASO therapeutics. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2024)

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17 pages, 3776 KB

Open AccessEditor’s ChoiceArticle

Molecular Markers Specific for the Pseudomonadaceae Genera Provide Novel and Reliable Means for the Identification of Other Pseudomonas Strains/spp. Related to These Genera

by Bashudev Rudra and Radhey S. Gupta

Genes 2025, 16(2), 183; https://doi.org/10.3390/genes16020183 - 2 Feb 2025

Cited by 2 | Viewed by 1719

Abstract

Background/Objectives: Taxon-specific conserved signature indels (CSIs) exhibit a strong predictive ability of being found in other members of specific taxa/genera. Recently, multiple exclusively shared CSIs were identified for several newly described Pseudomonadaceae genera (viz. Aquipseudomonas, Atopomonas, Caenipseudomonas, Chryseomonas Ectopseudomonas, [...] Read more.

Background/Objectives: Taxon-specific conserved signature indels (CSIs) exhibit a strong predictive ability of being found in other members of specific taxa/genera. Recently, multiple exclusively shared CSIs were identified for several newly described Pseudomonadaceae genera (viz. Aquipseudomonas, Atopomonas, Caenipseudomonas, Chryseomonas Ectopseudomonas, Geopseudomonas, Halopseudomonas, Metapseudomonas, Phytopseudomonas, Serpens, Stutzerimonas, Thiopseudomonas, and Zestomonas). This study examines the potential applications of these CSIs for identifying other Pseudomonas spp. (strains) related to these genera. Methods: This work utilized the AppIndels.com server, which uses information regarding the presence of known taxon-specific CSIs in a genome for predicting its taxonomic affiliation. For this purpose, sequence information for different CSIs specific for the Pseudomonadaceae species/genera were added to the server’s database. Results: The AppIndels server was used to predict the taxonomic affiliation of 1972 genomes of unclassified Pseudomonas spp. (strains/isolates). Based upon finding a significant number of CSIs matching a specific taxon, the AppIndels server made positive predictions regarding the taxonomic affiliation of 299 examined genomes into the following clades/genera: Pseudomonas sensu stricto clade (46), Pseudomonas aeruginosa (64), Ectopseudomonas (46), Chryseomonas (32), Stutzerimonas (31), Metapseudomonas (22), Aquipseudomonas (21), Phytopseudomonas (17), Halopseudomonas (9), Geopseudomonas (4), Thiopseudomonas (3), Serpens (2), and Caenipseudomonas and Zestomonas (1 each). Phylogenetic studies confirmed that the taxonomic predictions by the server were 100% accurate. Conclusions: Our results demonstrate that the CSIs specific for Pseudomonadaceae species/genera, in conjunction with the AppIndels server, provides a novel and useful tool for identifying other species/strains affiliated with these species/genera. Phylogenetic studies suggest that many examined Pseudomonas strains constitute novel species in the indicated genera. Full article

(This article belongs to the Special Issue Feature Papers in Microbial Genetics and Genomics)

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18 pages, 4427 KB

Open AccessEditor’s ChoiceArticle

An Actively Homing Insertion Element in a Phage Methylase Contains a Hidden HNH Endonuclease

by Danielle Arsenault, Sophia P. Gosselin and Johann Peter Gogarten

Genes 2025, 16(2), 178; https://doi.org/10.3390/genes16020178 - 1 Feb 2025

Cited by 1 | Viewed by 1480

Abstract

Background/Objectives: The ShiLan domain was previously identified as an insertion sequence in a phage DNA methylase gene that exhibited similar evolutionary patterns to that of an active intein or self-splicing intron but could not be identified as either. It produces no internal [...] Read more.

Background/Objectives: The ShiLan domain was previously identified as an insertion sequence in a phage DNA methylase gene that exhibited similar evolutionary patterns to that of an active intein or self-splicing intron but could not be identified as either. It produces no internal stop codons when read in frame with its host methylase gene, leading to the thought that it may not be an intron and rather be an abnormal type of intein. However, the sequence has no detectable self-splicing domains, which are essential for intein persistence, as preventing an intein from successfully splicing is often detrimental to proper host protein function. Methods: The analysis of alternate open reading frames for the full nucleotide sequence of this insertion element revealed the insertion to be an out-of-frame histidine-asparagine-histidine (HNH) endonuclease. A GTG start codon is located 18 bp into the insertion, and a TAA stop codon within the last four bases of the insertion (TAAC). When this frame is read, an HNH endonuclease is revealed. In-depth computational analysis could not retrieve support for this element being any known type of self-splicing element, neither intein nor intron. When read in-frame with the methylase gene, this insertion is predicted to take on a looping structure that may be able to avoid interference with the DNA methylase activity. We performed searches for sequences similar in nature to the inserted out-of-frame HNH and found several in other phages and prokaryotes. We present our survey of these out-of-frame endonuclease insertion elements as well as some speculation on how these endonucleases are getting translated to facilitate their homing activity. Conclusions: These findings expand our understanding of the possible arrangements for and prevalence of unorthodox mobile genetic elements and overlapping open reading frames in phages. Full article

(This article belongs to the Section Viral Genomics)

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9 pages, 1634 KB

Open AccessEditor’s ChoiceReview

Genetic Overlap of Thoracic Aortic Aneurysms and Intracranial Aneurysms

by Mah I Kan Changez, Afsheen Nasir, Alexandra Sonsino, Syeda Manahil Jeoffrey, Asanish Kalyanasundaram, Mohammad A. Zafar, Bulat A. Ziganshin and John A. Elefteriades

Genes 2025, 16(2), 154; https://doi.org/10.3390/genes16020154 - 26 Jan 2025

Cited by 1 | Viewed by 3325

Abstract

Objective: Thoracic aortic aneurysms (TAAs) and intracranial aneurysms (ICAs) share overlapping genetic and pathophysiological mechanisms, yet the genetic interplay between these conditions remains insufficiently explored. This study aimed to identify common genetic factors underlying TAA and ICA. Methods: A comprehensive review of genome-wide [...] Read more.

Objective: Thoracic aortic aneurysms (TAAs) and intracranial aneurysms (ICAs) share overlapping genetic and pathophysiological mechanisms, yet the genetic interplay between these conditions remains insufficiently explored. This study aimed to identify common genetic factors underlying TAA and ICA. Methods: A comprehensive review of genome-wide association studies (GWASs) and retrospective clinical studies was conducted using PubMed, Orbis, and Web of Science. Articles addressing the genetic etiologies of TAA and ICA were analyzed. Separate lists of causative genes were compiled, and commonalities were identified. A Venn diagram was constructed to illustrate genetic overlap and shared physiological pathways. Results: We identified 24 overlapping genes associated with TAA and ICA, including LTBP2, TGFB2, TGFB3, TGFBR1, TGFBR2, SMAD2, SMAD3, COL1A2, COL3A1, COL4A1, COL5A1, COL5A2, FBN1, FBN2, ELN, LOX ACTA2, MYH11, MYLK, ABCC6, NOTCH1, MED12, PKD1, and PKD2. These genes are involved in pathways related to connective tissue biology, contractile elements, extracellular matrix components, and transforming growth factor-β signaling. While vascular endothelium and cell cycle pathways were unique to ICA, TAA pathways predominantly involved extracellular matrix remodeling. Conclusions: This study highlights the significant genetic overlap between TAA and ICA, shedding light on shared molecular mechanisms. These findings underscore the importance of interdisciplinary awareness: neurologists, neurosurgeons, and neurointerventional radiologists should monitor ICA patients for potential TAA, while cardiologists, cardiac surgeons, vascular surgeons, and vascular interventionalists should consider ICA risks in TAA patients. Further research into these genetic pathways could enhance the understanding and management of both conditions. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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19 pages, 773 KB

Open AccessEditor’s ChoiceReview

Systematic Review: Fragile X Syndrome Across the Lifespan with a Focus on Genetics, Neurodevelopmental, Behavioral and Psychiatric Associations

by Ann C. Genovese and Merlin G. Butler

Genes 2025, 16(2), 149; https://doi.org/10.3390/genes16020149 - 25 Jan 2025

Cited by 6 | Viewed by 7582

Abstract

Background/Objectives: Fragile X syndrome (FXS) is one of the most common genetic causes of intellectual developmental disability and autism spectrum disorder (ASD), second only to Down’s syndrome and associated with a broad range of neurodevelopmental, behavioral, and psychiatric challenges. FXS may be present [...] Read more.

Background/Objectives: Fragile X syndrome (FXS) is one of the most common genetic causes of intellectual developmental disability and autism spectrum disorder (ASD), second only to Down’s syndrome and associated with a broad range of neurodevelopmental, behavioral, and psychiatric challenges. FXS may be present in infants or young children with characteristic dysmorphic features, developmental delays, and behavioral challenges. The diagnosis of FXS is confirmed by the molecular genetic testing of the FMR1 gene encoding fragile X messenger RNA-binding protein (FMRP), involved in regulating the translation of multiple mRNAs which play a key role in neuronal development and synaptic plasticity. Understanding the genetic cause, pathophysiology, and natural history of FXS is crucial for identifying commonly associated comorbidities, instituting effective therapeutic interventions, and improving long-term outcomes. Methods: This systematic review employed a comprehensive literature search using multiple electronic databases including PubMed, Web of Science, and Scopus with keywords related to fragile X syndrome, lifespan, genetics, neurodevelopmental, behavioral, and psychiatric disorders. Results: FXS is associated with an increased risk for specific neurodevelopmental, or psychiatric disorders. Symptoms and challenges associated with FXS vary based on multiple factors, including genetic differences, age, sex, comorbid conditions, various environmental influences, the availability of support, and opportunities for therapeutic interventions. Knowledge of these associations helps guide caregivers and clinicians in identifying potentially treatable conditions that can help to improve the lives of affected patients and their families. Conclusions: The focus of this article is to explore and describe the genetic underpinnings of FXS, identify associated developmental, behavioral, and psychiatric conditions over the lifespan, and provide a review of clinical features, therapeutic interventions including investigational treatments, and current research updates. Full article

(This article belongs to the Section Neurogenomics)

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23 pages, 4791 KB

Open AccessEditor’s ChoiceArticle

Combined Effect of Conventional Chemotherapy with Epigenetic Modulators on Glioblastoma

by Adrian Albulescu, Anca Botezatu, Alina Fudulu, Camelia Mia Hotnog, Marinela Bostan, Mirela Mihăilă, Iulia Virginia Iancu, Adriana Plesa and Lorelei Brasoveanu

Genes 2025, 16(2), 138; https://doi.org/10.3390/genes16020138 - 24 Jan 2025

Cited by 2 | Viewed by 1720

Abstract

Background/Objectives: Glioblastoma is the most common malignant primary brain tumor, characterized by necrosis, uncontrolled proliferation, infiltration, angiogenesis, apoptosis resistance, and genomic instability. Epigenetic modifiers hold promise as adjuvant therapies for gliomas, with synergistic combinations being explored to enhance efficacy and reduce toxicity. This [...] Read more.

Background/Objectives: Glioblastoma is the most common malignant primary brain tumor, characterized by necrosis, uncontrolled proliferation, infiltration, angiogenesis, apoptosis resistance, and genomic instability. Epigenetic modifiers hold promise as adjuvant therapies for gliomas, with synergistic combinations being explored to enhance efficacy and reduce toxicity. This study aimed to evaluate the effects of single or combined treatments with various anticancer drugs (Carboplatin, Paclitaxel, Avastin), natural compounds (Quercetin), and epigenetic modulators (suberoylanilide hydroxamic acid and 5-Azacytidine) on the expression of some long noncoding RNAs and methylation drivers or some functional features in the U87-MG cell line. Methods: Treated and untreated U87-MG cells were used for the evaluation of drug-induced cytotoxicity, apoptotic events, and distribution in cell cycle phases, detection of cytokine release, and assessment of gene expression and global methylation. Results: Cytotoxicity assays led to the selection of drug concentrations to be used in further experiments. Expression analysis revealed distinct downregulation of nearly all investigated genes and long noncoding RNAs following treatments. All treatments resulted in a higher percentage of global methylation compared to untreated controls. All treatments effectively increased levels of apoptosis, while the epigenetic modulators exhibited a lower proliferation profile, with combined treatments showing elevated values of cell lysis. Conclusions: The results indicate a link between Carboplatin and Avastin treatments and DNA methylation mechanisms involving EZH2, DNMT3A, and DNMT3B, with Avastin’s direct impact on these enzymes warranting further study. This research underscores the promise of platinum-based therapies combined with epigenetic drugs to reactivate silenced tumor suppressor genes and optimize methylation profiles. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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12 pages, 1459 KB

Open AccessEditor’s ChoiceArticle

Exploring miR-21 Knock-Out Using CRISPR/Cas as a Treatment for Lung Cancer

by Patricia Lara, Araceli Aguilar-González, Francisco Martín, Cristina Mesas, Javier Moreno and Ana R. Rama

Genes 2025, 16(2), 133; https://doi.org/10.3390/genes16020133 - 24 Jan 2025

Cited by 3 | Viewed by 2234

Abstract

Background: Lung cancer is a leading cause of cancer-related deaths worldwide. Its high incidence and poor prognosis demonstrate the need to investigate new therapies. The PI3K/AKT pathway is activated in carcinogenic processes such as invasion, proliferation, and drug resistance. MiR-21 is a microRNA [...] Read more.

Background: Lung cancer is a leading cause of cancer-related deaths worldwide. Its high incidence and poor prognosis demonstrate the need to investigate new therapies. The PI3K/AKT pathway is activated in carcinogenic processes such as invasion, proliferation, and drug resistance. MiR-21 is a microRNA overexpressed in numerous types of cancer and which activates PI3K/AKT pathway by down-regulating its main targets, PTEN and PDCD4. CRISPR is a revolutionary gene-editing technology that allows genes to be deleted. The aim of this study was to use CRISPR/Cas9 technology as an option to reduce carcinogenic and drug resistance processes by eliminating miR-21. Methods: CRISPR/Cas9 was used to knock out miR-21 (miR-21 KO) in A549 lung cancer cells and thus reverse the carcinogenic processes activated by miR-21 overexpression. Furthermore, the effect of miR-21 KO on drug resistance was studied, choosing the main chemotherapeutic agents used for the treatment of lung cancer: gemcitabine, carboplatin, paclitaxel, and oxaliplatin. Results: miR-21 KO A549 cells exhibited a reduction in proliferation, migration, and colony formation compared to A549 cells. In contrast, the expression of PTEN and PDCD4 increased in miR-21 KO A549 cells. Furthermore, miR-21 KO A549 cells showed a decrease in the IC₅₀ of the drugs used for the treatment of lung cancer: gemcitabine, carboplatin, paclitaxel, and oxaliplatin. Conclusions: Based on these results, miR-21 knock-out using CRISPR/Cas could be a promising strategy for the treatment of lung cancer. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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9 pages, 3855 KB

Open AccessEditor’s ChoiceArticle

16q24.3 Microdeletions Disrupting Upstream Non-Coding Region of ANKRD11 Cause KBG Syndrome

by Aiko Iwata-Otsubo, Alyssa L. Rippert, Jorune Balciuniene, Sarah K. Fiordaliso, Robert Chen, Preetha Markose, Cara M. Skraban, Christopher Gray, Elaine H. Zackai, Holly A Dubbs, Matthew A. Deardorff, Laura K. Conlin and Kosuke Izumi

Genes 2025, 16(2), 136; https://doi.org/10.3390/genes16020136 - 24 Jan 2025

Cited by 1 | Viewed by 1966

Abstract

Background: KBG syndrome is a multisystem developmental disorder characterized by macrodontia of the upper permanent incisors, distinctive facial features, a short stature, developmental delay, variable intellectual disability, and behavioral issues. Heterozygous chromosomal deletion encompassing the partial or entire ANKRD11 gene, as well as [...] Read more.

Background: KBG syndrome is a multisystem developmental disorder characterized by macrodontia of the upper permanent incisors, distinctive facial features, a short stature, developmental delay, variable intellectual disability, and behavioral issues. Heterozygous chromosomal deletion encompassing the partial or entire ANKRD11 gene, as well as the loss of function mutations, result in haploinsufficiency of the gene, leading to KBG syndrome. This indicates that precise levels of ANKRD11 transcripts or protein are essential for human development. Clinical report: Here, we report three individuals who present with clinical features of KBG syndrome. These individuals carry microdeletions encompassing only the non-coding exon 1 of ANKRD11 and its upstream region. Our molecular analysis showed that this deletion leads to reduction in the ANKRD11 transcript and global transcriptome alterations similar to those seen in KBG syndrome patients. Conclusions: We concluded that microdeletions involving non-coding exon 1 of ANKRD11 lead to KBG syndrome. Our study suggests the utility of transcriptome analysis in aiding the interpretation of novel copy number variants in the non-coding genomic region of ANKRD11. Full article

(This article belongs to the Special Issue The Genetic and Epigenetic Basis of Neurodevelopmental Disorders)

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15 pages, 801 KB

Open AccessEditor’s ChoiceReview

Syndromic and Non-Syndromic Primary Failure of Tooth Eruption: A Genetic Overview

by Clarissa Modafferi, Elisabetta Tabolacci, Cristina Grippaudo and Pietro Chiurazzi

Genes 2025, 16(2), 147; https://doi.org/10.3390/genes16020147 - 24 Jan 2025

Cited by 3 | Viewed by 3735

Abstract

Primary failure of tooth eruption (PFE) is a rare genetic disorder characterized by the failure of teeth to erupt in the absence of obvious physical obstructions, often resulting in a progressive open bite that is resistant to orthodontic treatment. While PFE can be [...] Read more.

Primary failure of tooth eruption (PFE) is a rare genetic disorder characterized by the failure of teeth to erupt in the absence of obvious physical obstructions, often resulting in a progressive open bite that is resistant to orthodontic treatment. While PFE can be caused by genetic or systemic factors (such as cysts, tumors, and endocrine imbalances), the non-syndromic causes are primarily genetic, with an autosomal dominant inheritance pattern with variable expressivity. Several genes have been closely associated with the non-syndromic PFE form. The PTH1R (parathyroid hormone 1 receptor) is the most commonly PFE-associated gene. Additional genes associated with minor frequency are Transmembrane protein 119 (TMEM119), which reduces the glycolytic efficiency of bone cells, limiting their mineralization capacity and causing bone fragility; Periostin (POSTN), which regulates the extracellular matrix and the bone’s response to mechanical stress; and Lysine (K)-specific methyltransferase 2C (KMT2C), which establishes histone methylation near the Wnt Family Member 5A (WNT5A) gene involved in dental development (odontogenesis). Syndromic forms of PFE are typically associated with complex multisystem disorders, where dental eruption failure is one of the clinical features of the spectrum. These syndromes are often linked to genetic variants that affect ectodermal development, craniofacial patterning, and skeletal growth, leading to abnormal tooth development and eruption patterns. Notable syndromes include GAPO syndrome, ectodermal dysplasia, and cleidocranial dysplasia, each contributing to PFE through distinct molecular mechanisms, such as disruptions in dental structure development, cranial abnormalities, or systemic developmental delays. The main aim of this review is to provide a comprehensive overview of the genetic basis underlying both syndromic and non-syndromic forms of PFE to facilitate precision diagnosis, foster the development of personalized therapeutic strategies, and offer new insights into managing this complex dental anomaly. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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9 pages, 201 KB

Open AccessEditor’s ChoiceArticle

The Prevalence of Single Nucleotide Polymorphisms of the AOC1 Gene Associated with Diamine Oxidase (DAO) Enzyme Deficiency in Healthy Newborns: A Prospective Population-Based Cohort Study

by Emma Fortes Marin, Lydia Carrera Marcolin, Laia Martí Melero, María Tintoré Gazulla and Mireia Beltran Porres

Genes 2025, 16(2), 141; https://doi.org/10.3390/genes16020141 - 24 Jan 2025

Cited by 5 | Viewed by 3428

Abstract

Background/Objectives: The prevalence of the diamine oxidase (DAO) enzyme deficiency of a genetic origin has not been previously assessed. A prospective population-based study was conducted in a sample of 200 healthy newborns aimed to determine the prevalence of DAO enzyme deficiency caused by [...] Read more.

Background/Objectives: The prevalence of the diamine oxidase (DAO) enzyme deficiency of a genetic origin has not been previously assessed. A prospective population-based study was conducted in a sample of 200 healthy newborns aimed to determine the prevalence of DAO enzyme deficiency caused by single nucleotide polymorphism (SNP) variants of the AOC1 gene. Methods: Genotyping was performed in oral mucosa samples collected around 2 days after birth. The four more frequent SNPs, c.47C>T (rs10156191), c.995C>T (rs1049742), c.1990C>G (rs10449793), and c.691G>T (rs2052129), were analyzed. Results: DAO deficiency was present in 132 newborns, with a prevalence of 66% (95% confidence interval [CI] 59–73%). The rs10449793 variant showed a prevalence of 46%, followed by rs10156191 with a prevalence of 42.5%, and rs2052129 with a prevalence of 39.5%. The variant rs1049742 showed the lowest prevalence (9.5%). The frequency of one, two, three, or four SNPs was 23%, 23.5%, 10.5%, and 9%, respectively. In all fours SNP variants, heterozygous carriers were more frequent than homozygous carriers (19% homozygosity). Differences in the prevalence of DAO deficiency between males (68%, 66/96) and females (63.4%, 66/104) were not found (p = 0.885). The prevalence in Caucasian newborns was 66.5% (123/185), as compared with 60% (9/15) in Latin Americans (p = 0.821). Conclusions: This study carried out in healthy newborns indicates that there is a high prevalence (66%) of DAO deficiency of a genetic origin in the general population. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

22 pages, 1291 KB

Open AccessEditor’s ChoiceReview

Trophectoderm Biopsy: Present State of the Art

by Anick De Vos and Neelke De Munck

Genes 2025, 16(2), 134; https://doi.org/10.3390/genes16020134 - 24 Jan 2025

Cited by 6 | Viewed by 6790

Abstract

Trophectoderm (TE) biopsy is at present the most widely used procedure for preimplantation genetic testing (PGT). At the blastocyst stage, more TE cells (five to seven) can be obtained for genetic analysis. While removing TE cells and not touching the inner cell mass [...] Read more.

Trophectoderm (TE) biopsy is at present the most widely used procedure for preimplantation genetic testing (PGT). At the blastocyst stage, more TE cells (five to seven) can be obtained for genetic analysis. While removing TE cells and not touching the inner cell mass (ICM), the procedure is less invasive. Due to a natural selection happening between day 3 and day 5, 6 or 7 of human embryo development, fewer embryos will have to be biopsied and tested. An additional benefit, especially in view of aneuploidy testing (PGT-A), is the lower level of mosaicism present at the blastocyst stage. The biopsy procedure involves two steps: laser-assisted zona pellucida (ZP) opening and the excision of five to eight TE cells from the blastocyst with or without additional laser energy. Different protocols have emerged over time with variations regarding the technique, the exact moment of ZP opening, and the method of cell removal. The ‘pulling’ method involves laser excision, whereas the ‘flicking’ method represents a mechanical approach with or without laser assistance. Embryo developmental speed reaching the full/expanded or hatching/hatched blastocyst stage dictates the timing of the procedure, mostly on day 5 post-insemination, and to a lesser extent on day 6 or even on day 7. The inclusion of lesser quality or delayed blastocysts may impact the quality of the TE sample as well as the clinical outcome. Intracytoplasmic sperm injection (ICSI) is still the preferred method of fertilization for PGT-M (monogenic disorders) and PGT-SR (structural rearrangements). However, conventional in vitro fertilization (IVF) seems feasible for PGT-A (aneuploidy testing). In the absence of a (conclusive) genetic result, the re-biopsy of cryopreserved blastocysts is possible, however, with reduced clinical outcomes. So far, neonatal outcome post-TE biopsy has so far been reassuringly documented. Full article

(This article belongs to the Special Issue Current Advances and Future Perspectives on Preimplantation Genetic Testing)

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23 pages, 3914 KB

Open AccessEditor’s ChoiceReview

Genomic and Transcriptomic Approaches Advance the Diagnosis and Prognosis of Neurodegenerative Diseases

by Zheng Liu and Si-Yuan Song

Genes 2025, 16(2), 135; https://doi.org/10.3390/genes16020135 - 24 Jan 2025

Cited by 11 | Viewed by 4744

Abstract

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression and significant impact on patients, caregivers, and healthcare systems. Despite advances in clinical and imaging-based [...] Read more.

Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), represent a growing societal challenge due to their irreversible progression and significant impact on patients, caregivers, and healthcare systems. Despite advances in clinical and imaging-based diagnostics, these diseases are often detected at advanced stages, limiting the effectiveness of therapeutic interventions. Recent breakthroughs in genomic and transcriptomic technologies, including whole-genome sequencing, single-cell RNA sequencing (scRNA-seq), and CRISPR-based screens, have revolutionized the field, offering new avenues for early diagnosis and personalized prognosis. Genomic approaches have elucidated disease-specific genetic risk factors and molecular pathways, while transcriptomic studies have identified stage-specific biomarkers that correlate with disease progression and severity. Furthermore, genome-wide association studies (GWAS), polygenic risk scores (PRS), and spatial transcriptomics are enabling the stratification of patients based on their risk profiles and prognostic trajectories. Advances in functional genomics have uncovered actionable targets, such as ATXN2 in ALS and TREM2 in AD, paving the way for tailored therapeutic strategies. Despite these achievements, challenges remain in translating genomic discoveries into clinical practice due to disease heterogeneity and the complexity of neurodegenerative pathophysiology. Future integration of genetic technologies holds promise for transforming diagnostic and prognostic paradigms, offering hope for improved patient outcomes and precision medicine approaches. Full article

(This article belongs to the Special Issue Genomic Approaches for Disease Diagnosis and Prognosis)

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20 pages, 4939 KB

Open AccessEditor’s ChoiceArticle

Genome-Wide Identification and Characterization of Histone Acetyltransferases and Deacetylases in Cucumber, and Their Implication in Developmental Processes

by Agnieszka Skarzyńska-Łyżwa, Szymon Turek, Maksymilian Pisz, Aparna, Wojciech Pląder and Magdalena Pawełkowicz

Genes 2025, 16(2), 127; https://doi.org/10.3390/genes16020127 - 23 Jan 2025

Cited by 1 | Viewed by 1362

Abstract

Background/Objectives: Cucumber (Cucumis sativus) provides a model for exploring the molecular basis of sex determination, particularly the regulation of floral organ differentiation through gene expression. This complex process is modulated by epigenetic factors, such as histone acetyltransferases (HATs) and histone deacetylases [...] Read more.

Background/Objectives: Cucumber (Cucumis sativus) provides a model for exploring the molecular basis of sex determination, particularly the regulation of floral organ differentiation through gene expression. This complex process is modulated by epigenetic factors, such as histone acetyltransferases (HATs) and histone deacetylases (HDACs), which respectively activate and repress gene transcription by adding or removing acetyl groups from histone proteins. Despite their known functions, the roles of HATs and HDACs throughout cucumber’s floral developmental stages remain unclear. Methods: In this study, we conducted a genome-wide analysis of HAT and HDAC gene families in cucumber, examining their phylogenetic relationships, gene structures, protein domains, and expression profiles across various stages of floral development. Results: We identified 36 CsHAT and 12 CsHDAC genes, grouping them into families with evolutionary counterparts in other plant species. RNA sequencing revealed stage-specific expression patterns, suggesting dynamic roles for these gene families in floral organ development. Conclusions: These findings contribute valuable insights into the epigenetic regulation of gene expression in cucumber flower formation, presenting avenues for further research on the genetic control of plant reproductive development. Full article

(This article belongs to the Section Plant Genetics and Genomics)

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23 pages, 1040 KB

Open AccessEditor’s ChoiceReview

The Impact of Klotho in Cancer: From Development and Progression to Therapeutic Potential

by Miguel A. Ortega, Diego Liviu Boaru, Diego De Leon-Oliva, Patricia De Castro-Martinez, Ana M. Minaya-Bravo, Carlos Casanova-Martín, Silvestra Barrena-Blázquez, Cielo Garcia-Montero, Oscar Fraile-Martinez, Laura Lopez-Gonzalez, Miguel A. Saez, Melchor Alvarez-Mon and Raul Diaz-Pedrero

Genes 2025, 16(2), 128; https://doi.org/10.3390/genes16020128 - 23 Jan 2025

Cited by 5 | Viewed by 4043

Abstract

Klotho, initially identified as an anti-aging gene, has been shown to play significant roles in cancer biology. Alongside α-Klotho, the β-Klotho and γ-Klotho isoforms have also been studied; these studies showed that Klotho functions as a potential tumor suppressor in many different cancers [...] Read more.

Klotho, initially identified as an anti-aging gene, has been shown to play significant roles in cancer biology. Alongside α-Klotho, the β-Klotho and γ-Klotho isoforms have also been studied; these studies showed that Klotho functions as a potential tumor suppressor in many different cancers by inhibiting cancer cell proliferation, inducing apoptosis and modulating critical signaling pathways such as the Wnt/β-catenin and PI3K/Akt pathways. In cancers such as breast cancer, colorectal cancer, hepatocellular carcinoma, ovarian cancer, and renal cell carcinoma, reduced Klotho expression often correlates with a poor prognosis. In addition, Klotho’s role in enhancing chemotherapy sensitivity and its epigenetic regulation further underscores its potential as a target for cancer treatments. This review details Klotho’s multifaceted contributions to cancer suppression and its potential as a therapeutic target, enhancing the understanding of its significance in cancer treatment and prognoses. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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16 pages, 1636 KB

Open AccessEditor’s ChoiceArticle

MicroRNAs miR-148a-3p, miR-425-3p, and miR-20a-5p in Patients with IgA Nephropathy

by Jarosław Przybyciński, Michał Czerewaty, Ewa Kwiatkowska, Violetta Dziedziejko, Krzysztof Safranow, Leszek Domański and Andrzej Pawlik

Genes 2025, 16(2), 125; https://doi.org/10.3390/genes16020125 - 23 Jan 2025

Cited by 2 | Viewed by 1337

Abstract

Background/Objectives: IgA nephropathy (IgAN) is one of the most common forms of glomerulonephritis leading to renal failure. MicroRNAs have been shown to play an important role in the pathogenesis and clinical course of IgA nephropathy; therefore, they offer the possibility of noninvasive diagnosis [...] Read more.

Background/Objectives: IgA nephropathy (IgAN) is one of the most common forms of glomerulonephritis leading to renal failure. MicroRNAs have been shown to play an important role in the pathogenesis and clinical course of IgA nephropathy; therefore, they offer the possibility of noninvasive diagnosis of this disease and have some value in predicting disease prognosis. This study aimed to evaluate the plasma levels of miR-148a-3p, miR-425-3p, and miR-20a-5p in patients with IgA nephropathy and their correlation with selected clinical parameters. Methods: This study included 44 patients with IgA nephropathy and 46 control subjects. Results: The results of our study indicated that in patients with IgA nephropathy, the increased plasma levels of miR-148a-3p and miR-425-3p correlated negatively with eGFR values. According to the Haas classification, plasma levels of miR-20a-5p were statistically significantly increased in patients with histopathological changes classified as Stages 3, 4, and 5 compared with patients with histopathological changes classified as Stages 1 and 2. Conclusions: The results of our study suggest the possible involvement of miR-148a-3p, miR-425-3p, and miR-20a-5p in the pathogenesis of IgA nephropathy. Full article

(This article belongs to the Special Issue Epigenetics in Human Development and Diseases)

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11 pages, 629 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Comparative Analysis of Genomic and Pedigree-Based Approaches for Genetic Evaluation of Morphological Traits in Pura Raza Española Horses

by Chiraz Ziadi, Sebastián Demyda-Peyrás, Mercedes Valera, Davinia Perdomo-González, Nora Laseca, Arancha Rodríguez-Sainz de los Terreros, Ana Encina, Pedro Azor and Antonio Molina

Genes 2025, 16(2), 131; https://doi.org/10.3390/genes16020131 - 23 Jan 2025

Cited by 3 | Viewed by 2030

Abstract

Background: The single-step best linear unbiased predictor (ssGBLUP) has emerged as a reference method for genomic selection in recent years due to its advantages over traditional approaches. Although its application in horses remains limited, ssGBLUP has demonstrated the potential to improve the reliability [...] Read more.

Background: The single-step best linear unbiased predictor (ssGBLUP) has emerged as a reference method for genomic selection in recent years due to its advantages over traditional approaches. Although its application in horses remains limited, ssGBLUP has demonstrated the potential to improve the reliability of estimated breeding values in livestock species. This study aimed to assess the impact of incorporating genomic data using single-step restricted maximum likelihood (ssGREML) on reliability (R²) in the Pura Raza Española (PRE) horse breed, compared to traditional pedigree-based REML. Methods: The analysis involved 14 morphological traits from 7152 animals, including 2916 genotyped individuals. Genetic parameters were estimated using a multivariate model. Results: Results showed that heritability estimates were similar between the two approaches, ranging from 0.08 to 0.76. However, a significant increase in reliability (R²) was observed for ssGREML compared to REML across all morphological traits, with overall gains ranging from 1.56% to 13.30% depending on the trait evaluated. R² ranged from 6.93% to 22.70% in genotyped animals, significantly lower in non-genotyped animals (0.82% to 12.37%). Interestingly, individuals with low R² values in REML demonstrated the largest R² gains in ssGREML. Additionally, this improvement was much greater (5.96% to 19.25%) when only considering stallions with less than 40 controlled foals. Conclusions: Hereby, we demonstrated that the application of genomic selection can contribute to improving the reliability of mating decisions in a large horse breeding program such as the PRE breed. Full article

(This article belongs to the Section Animal Genetics and Genomics)

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15 pages, 1631 KB

Open AccessEditor’s ChoiceArticle

Comparative Study of Statistical Approaches and SNP Panels to Infer Distant Relationships in Forensic Genetics

by Andreas Tillmar and Daniel Kling

Genes 2025, 16(2), 114; https://doi.org/10.3390/genes16020114 - 21 Jan 2025

Cited by 5 | Viewed by 2096

Abstract

Background/Objectives: Inferring genetic relationships based on genetic data has gained an increasing focus in the last years, in particular explained by the rise of forensic investigative genetic genealogy (FIGG) but also the introduction of expanded SNP panels in forensic genetics. A plethora [...] Read more.

Background/Objectives: Inferring genetic relationships based on genetic data has gained an increasing focus in the last years, in particular explained by the rise of forensic investigative genetic genealogy (FIGG) but also the introduction of expanded SNP panels in forensic genetics. A plethora of statistical methods are used throughout publications; in direct-to-consumer (DTC) testing, the shared segment approach is used, in screenings of relationships in medical genetic research, for instance, methods-of-moment estimators, e.g., estimation of the kinship coefficient, are used, and in forensic genetics, the likelihood and the likelihood ratio are commonly used to evaluate the genetic data under competing hypotheses. This current study aims to compare and contrast examples of the aforementioned statistical methods to infer relationships from genetic data. Methods/Results: This study includes some historical and some recently published panels of SNP markers to illustrate the strength and caveats of the statistical methods on different marker sets and a selection of pre-defined pairwise relationships, 1st through 7th degree. Extensive simulations are performed and subsequently subsetted based on the marker panels alluded to above. As has been shown in previous research, the likelihood ratio is most powerful, i.e., high correct classifications, when SNP data are sparse, say below 20,000 markers, whereas the windowed kinships and segment approaches are equally powerful when very dense SNP data are available, say >20,000 markers. In between lay approaches using method-of-moments estimators which perform well when the degree of relationship is below four but less so beyond, say, 4th degree relationships. The likelihood ratio is the only method that is easily adapted for non-pairwise tests and therefore has an additional depth not addressed in the current study. We furthermore perform a study of genotyping error rates and their impact on the different statistical methods employed to infer relationships, where the results show that error rates below 1% seem to have low impact across all methods, in particular for errors yielding false heterozygote genotypes. Full article

(This article belongs to the Special Issue Forensic Genetics: Human DNA Database and Genetic Structure)

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20 pages, 1552 KB

Open AccessEditor’s ChoiceArticle

Further Development of SAMPDI-3D: A Machine Learning Method for Predicting Binding Free Energy Changes Caused by Mutations in Either Protein or DNA

by Prawin Rimal, Shamrat Kumar Paul, Shailesh Kumar Panday and Emil Alexov

Genes 2025, 16(1), 101; https://doi.org/10.3390/genes16010101 - 19 Jan 2025

Cited by 4 | Viewed by 2142

Abstract

Background/Objectives: Predicting the effects of protein and DNA mutations on the binding free energy of protein–DNA complexes is crucial for understanding how DNA variants impact wild-type cellular function. As many cellular interactions involve protein–DNA binding, accurately predicting changes in binding free energy (ΔΔG) [...] Read more.

Background/Objectives: Predicting the effects of protein and DNA mutations on the binding free energy of protein–DNA complexes is crucial for understanding how DNA variants impact wild-type cellular function. As many cellular interactions involve protein–DNA binding, accurately predicting changes in binding free energy (ΔΔG) is valuable for distinguishing pathogenic mutations from benign ones. Methods: This study describes the development and optimization of the SAMPDI-3Dv2 machine learning method, which is trained on an expanded database of experimentally measured ΔΔGs. This enhanced model incorporates new features, including the 3D structure of the mutant protein, features of the mutant structure, and a position-specific scoring matrix (PSSM). Benchmarking was conducted using 5-fold cross-validation. Results: The updated SAMPDI-3D model (SAMPDI-3Dv2) achieved Pearson correlation coefficients (PCCs) of 0.68 for protein and 0.80 for DNA mutations. These results represent significant improvements over existing tools. Additionally, the method’s rapid execution time enables genome-scale predictions. Conclusions: The improved SAMPDI-3Dv2 shows enhanced predictive performance for analyzing mutations in protein–DNA complexes. By leveraging structural information and an expanded training dataset, SAMPDI-3Dv2 provides researchers with a more accurate and efficient tool for mutation analysis, contributing to identifying pathogenic variants and improving our understanding of cellular function. Full article

(This article belongs to the Section Technologies and Resources for Genetics)

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13 pages, 223 KB

Open AccessEditor’s ChoiceReview

History of Biological Databases, Their Importance, and Existence in Modern Scientific and Policy Context

by Mikołaj Danielewski, Marlena Szalata, Jan Krzysztof Nowak, Jarosław Walkowiak, Ryszard Słomski and Karolina Wielgus

Genes 2025, 16(1), 100; https://doi.org/10.3390/genes16010100 - 18 Jan 2025

Cited by 1 | Viewed by 3340

Abstract

With the development of genome sequencing technologies, the amount of data produced has greatly increased in the last two decades. The abundance of digital sequence information (DSI) has provided research opportunities, improved our understanding of the genome, and led to the discovery of [...] Read more.

With the development of genome sequencing technologies, the amount of data produced has greatly increased in the last two decades. The abundance of digital sequence information (DSI) has provided research opportunities, improved our understanding of the genome, and led to the discovery of new solutions in industry and medicine. It has also posed certain challenges, i.e., how to store and handle such amounts of data. This, coupled with the need for convenience, international cooperation, and the possibility of independent validation, has led to the establishment of numerous databases. Spearheaded with the idea that data obtained with public funds should be available to the public, open access has become the predominant mode of accession. However, the increasing popularity of commercial genetic tests brings back the topic of data misuse, and patient’s privacy. At the previous United Nations Biodiversity Conference (COP15, 2022), an issue of the least-developed countries exploiting their natural resources while providing DSI and the most-developed countries benefitting from this was raised. It has been proposed that financial renumeration for the data could help protect biodiversity. With the goal of introducing the topic to those interested in utilizing biological databases, in this publication, we present the history behind the biological databases, their necessity in today’s scientific world, and the issues that concern them and their content, while providing scientific and policy context in relation to United Nations Biodiversity Conference (COP16, 21.10—1.11.24). Full article

(This article belongs to the Section Bioinformatics)

22 pages, 955 KB

Open AccessEditor’s ChoiceReview

Hallmarks of DNA Damage Response in Germination Across Model and Crop Species

by Federico Sincinelli, Shraddha Shridhar Gaonkar, Sri Amarnadh Gupta Tondepu, Conrado Jr Dueñas and Andrea Pagano

Genes 2025, 16(1), 95; https://doi.org/10.3390/genes16010095 - 17 Jan 2025

Cited by 4 | Viewed by 2647

Abstract

DNA damage response (DDR) contributes to seed quality by guarding genome integrity in the delicate phases of pre- and post-germination. As a key determinant of stress tolerance and resilience, DDR has notable implications on the wider scale of the agroecosystems challenged by harsh [...] Read more.

DNA damage response (DDR) contributes to seed quality by guarding genome integrity in the delicate phases of pre- and post-germination. As a key determinant of stress tolerance and resilience, DDR has notable implications on the wider scale of the agroecosystems challenged by harsh climatic events. The present review focuses on the existing and documented links that interconnect DDR efficiency with an array of molecular hallmarks with biochemical, molecular, and physiological valence within the seed metabolic networks. The expression of genes encoding DDR sensors, transducers, mediators, and effectors is interpreted as a source of conserved hallmarks, along with markers of oxidative damage reflecting the seed’s ability to germinate. Similarly, the accumulation patterns of proteins and metabolites that contribute to DNA stability are predictive of seed quality traits. While a list of candidates is presented from multiple models and crop species, their interaction with chromatin dynamics, cell cycle progression, and hormonal regulation provides further levels of analysis to investigate the seed stress response holistically. The identification of novel hallmarks of DDR in seeds constitutes a framework to prompt validation with different experimental systems, to refine the current models of pre-germinative metabolism, and to promote targeted approaches for seed quality evaluation. Full article

(This article belongs to the Special Issue DNA Damage Repair and Plant Stress Response)

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19 pages, 3458 KB

Open AccessEditor’s ChoiceArticle

Casein Kinase I Protein Hrr25 Is Required for Pin4 Phosphorylation and Mediates Cell Wall Integrity Signaling in Saccharomyces cerevisiae

by Amita Bhattarai, Manika Bhondeley and Zhengchang Liu

Genes 2025, 16(1), 94; https://doi.org/10.3390/genes16010094 - 17 Jan 2025

Cited by 1 | Viewed by 1721

Abstract

Background: Casein kinase I protein Hrr25 plays important roles in many cellular processes, including autophagy, vesicular trafficking, ribosome biogenesis, mitochondrial biogenesis, and the DNA damage response in Saccharomyces cerevisiae. Pin4 is a multi-phosphorylated protein that has been reported to be involved in [...] Read more.

Background: Casein kinase I protein Hrr25 plays important roles in many cellular processes, including autophagy, vesicular trafficking, ribosome biogenesis, mitochondrial biogenesis, and the DNA damage response in Saccharomyces cerevisiae. Pin4 is a multi-phosphorylated protein that has been reported to be involved in the cell wall integrity (CWI) pathway and DNA damage response. Pin4 was reported to interact with Hrr25 in yeast two-hybrid and large-scale pulldown assays. Methods/Objectives: Co-immunoprecipitation and yeast two-hybrid assays were utilized to confirm whether Pin4 and Hrr25 interact and to determine how they interact. Genetic interaction analysis was conducted to examine whether hrr25 mutations form synthetic growth defects with mutations in genes involved in CWI signaling. Immunoblotting was used to determine whether Hrr25 phosphorylates Pin4. Results: We show that Hrr25 interacts with Pin4 and is required for Pin4 phosphorylation. pin4 mutations result in synthetic slow-growth phenotypes with mutations in genes encoding Bck1 and Slt2, two of the protein kinases in the MAP kinase cascade that regulates CWI in the budding yeast. We show that hrr25 mutations result in similar phenotypes to pin4 mutations. Hrr25 consists of an N-terminal kinase domain, a middle region, and a C-terminal proline/glutamine-rich domain. The function of the C-terminal P/Q-rich domain of Hrr25 has been elusive. We found that the C-terminal region of Hrr25 is required both for Pin4 interaction and CWI. Conclusions: Our data suggest that Hrr25 is implicated in cell wall integrity signaling via its association with Pin4. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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14 pages, 2311 KB

Open AccessEditor’s ChoiceArticle

Identifying Genetic Predisposition to Dozer Lamb Syndrome: A Semi-Lethal Muscle Weakness Disease in Sheep

by Morgan R. Stegemiller, Margaret A. Highland, Kathleen M. Ewert, Holly Neaton, David S. Biller and Brenda M. Murdoch

Genes 2025, 16(1), 83; https://doi.org/10.3390/genes16010083 - 14 Jan 2025

Cited by 1 | Viewed by 1453

Abstract

Background: Lamb health is crucial for producers; however, the percentage of lambs that die before weaning is still 15–20%. One factor that can contribute to lamb deaths is congenital diseases. A novel semi-lethal disease has been identified in newborn Polypay lambs and termed [...] Read more.

Background: Lamb health is crucial for producers; however, the percentage of lambs that die before weaning is still 15–20%. One factor that can contribute to lamb deaths is congenital diseases. A novel semi-lethal disease has been identified in newborn Polypay lambs and termed dozer lamb syndrome. This study aims to determine if there is a genetic predisposition to dozer lamb syndrome. These lambs are weak and unable to lift their heads, suckle, and swallow, resulting in nasal reflux. Methods: Genetic analyses, including a genome-wide association, runs of homozygosity, and fine mapping to determine haploblock within regions of interest, were utilized in determining genetic predispositions to dozer lamb syndrome. Results: The genome-wide association study identified a region of chromosome 15 with three significant SNPs (p-values of 6.81 × 10⁻⁶, 5.71 × 10⁻⁶, and 8.52 × 10⁻⁶). Genetic analysis identified a run of homozygosity on the same region of chromosome 15 with an odds ratio of 236.7. Fine mapping of this region identified three haploblocks associated with the dozer lamb syndrome (p-value = 2.41 × 10⁻⁵). Conclusions: The most significant and promising gene in this region is CELF1, which is known to play an important role in muscle development. Abnormal CELF1 abundance and cellular location are reported to result in abnormal muscle development. Identification of genetic aberrations associated with dozer lamb syndrome provides a tool for decreasing or eliminating the genotype and, thus, the associated phenotype(s) from Polypay sheep. Full article

(This article belongs to the Section Animal Genetics and Genomics)

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14 pages, 3490 KB

Open AccessEditor’s ChoiceArticle

Evaluation of Genetic Diversity and Identification of Cultivars in Spray-Type Chrysanthemum Based on SSR Markers

by Manjulatha Mekapogu, So-Hyeon Lim, Youn-Jung Choi, Su-Young Lee and Jae-A Jung

Genes 2025, 16(1), 81; https://doi.org/10.3390/genes16010081 - 13 Jan 2025

Cited by 2 | Viewed by 2356

Abstract

Background/Objectives: Chrysanthemum (Chrysanthemum morifolium), a key ornamental and medicinal plant, presents challenges in cultivar identification due to high phenotypic similarity and environmental influences. This study assessed the genetic diversity and discrimination of 126 spray-type chrysanthemum cultivars. Methods: About twenty-three simple sequence [...] Read more.

Background/Objectives: Chrysanthemum (Chrysanthemum morifolium), a key ornamental and medicinal plant, presents challenges in cultivar identification due to high phenotypic similarity and environmental influences. This study assessed the genetic diversity and discrimination of 126 spray-type chrysanthemum cultivars. Methods: About twenty-three simple sequence repeat (SSR) markers were screened for the discrimination of 126 cultivars, among which six SSR markers showed polymorphic fragments. Results: Results showed high polymorphism across six markers, with an average of 3.8 alleles per locus and a mean polymorphism information content (PIC) of 0.52, indicating strong discriminatory efficiency. The average observed heterozygosity (Ho) was 0.72, reflecting significant genetic diversity within the cultivars. Cluster analysis using the unweighted pair group method with arithmetic mean (UPGMA) grouped the cultivars into seven clusters, correlating well with the PCA. Bayesian population structure analysis suggested two primary genetic subpopulations. Conclusions: These findings confirm SSR markers as an effective tool for the genetic characterization and precise discrimination of spray type chrysanthemum cultivars, offering significant applications in breeding, cultivar registration, and germplasm conservation. The SSR marker-based approach thus provides a reliable and efficient strategy to enhance the management and commercialization of diverse chrysanthemum germplasm collections. Full article

(This article belongs to the Special Issue Genetics and Breeding of Ornamental Plants)

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29 pages, 575 KB

Open AccessEditor’s ChoiceReview

Hereditary Breast Cancer: Comprehensive Risk Assessment and Prevention Strategies

by Eliza Del Fiol Manna, Davide Serrano, Laura Cazzaniga, Sara Mannucci, Cristina Zanzottera, Francesca Fava, Gaetano Aurilio, Aliana Guerrieri-Gonzaga, Matilde Risti, Mariarosaria Calvello, Irene Feroce, Monica Marabelli, Cecilia Altemura, Lucio Bertario, Bernardo Bonanni and Matteo Lazzeroni

Genes 2025, 16(1), 82; https://doi.org/10.3390/genes16010082 - 13 Jan 2025

Cited by 4 | Viewed by 6786

Abstract

Women carrying pathogenic/likely pathogenic (P/LP) variants in moderate- or high-penetrance genes have an increased risk of developing breast cancer. However, most P/LP variants associated with breast cancer risk show incomplete penetrance. Age, gender, family history, polygenic risk, lifestyle, reproductive, hormonal, and environmental factors [...] Read more.

Women carrying pathogenic/likely pathogenic (P/LP) variants in moderate- or high-penetrance genes have an increased risk of developing breast cancer. However, most P/LP variants associated with breast cancer risk show incomplete penetrance. Age, gender, family history, polygenic risk, lifestyle, reproductive, hormonal, and environmental factors can affect the expressivity and penetrance of the disease. However, there are gaps in translating how individual genomic variation affects phenotypic presentation. The expansion of criteria for genetic testing and the increasing utilization of comprehensive genetic panels may enhance the identification of individuals carrying P/LP variants linked to hereditary breast cancer. Individualized risk assessment could facilitate the implementation of personalized risk-reduction strategies for these individuals. Preventive interventions encompass lifestyle modifications, chemoprevention, enhanced surveillance through breast imaging, and risk-reducing surgeries. This review addresses the current literature’s inconsistencies and limitations, particularly regarding risk factors and the intensity of preventive strategies for women with P/LP variants in moderate- and high-penetrance genes. In addition, it synthesizes the latest evidence on risk assessment and primary and secondary prevention in women at high risk of breast cancer. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

16 pages, 3571 KB

Open AccessEditor’s ChoiceArticle

Chromosome 4 Duplication Associated with Strabismus Leads to Gene Expression Changes in iPSC-Derived Cortical Neurons

by Mayra Martinez-Sanchez, William Skarnes, Ashish Jain, Sampath Vemula, Liang Sun, Shira Rockowitz and Mary C. Whitman

Genes 2025, 16(1), 80; https://doi.org/10.3390/genes16010080 - 12 Jan 2025

Cited by 1 | Viewed by 1929

Abstract

Background/Objectives: Strabismus is the most common ocular disorder of childhood. Three rare, recurrent genetic duplications have been associated with both esotropia and exotropia, but the mechanisms by which they contribute to strabismus are unknown. This work aims to investigate the mechanisms of the [...] Read more.

Background/Objectives: Strabismus is the most common ocular disorder of childhood. Three rare, recurrent genetic duplications have been associated with both esotropia and exotropia, but the mechanisms by which they contribute to strabismus are unknown. This work aims to investigate the mechanisms of the smallest of the three, a 23 kb duplication on chromosome 4 (hg38|4:25,554,985-25,578,843). Methods: Using CRISPR and bridging oligos, we introduced the duplication into the Kolf2.1J iPSC line. We differentiated the parent line and the line with the duplication into cortical neurons using a three-dimensional differentiation protocol, and performed bulk RNASeq on neural progenitors (day 14) and differentiated neurons (day 63). Results: We successfully introduced the duplication into Kolf2.1J iPSCs by nucleofecting a bridging oligo for the newly formed junction along with cas9 ribonucleoparticles. We confirmed that the cells had a tandem duplication without inversion or deletion. The parent line and the line with the duplication both differentiated into neurons reliably. There were a total of 37 differentially expressed genes (DEGs) at day 63, 25 downregulated and 12 upregulated. There were 55 DEGs at day 14, 18 of which were also DEGs at day 63. The DEGs included a number of protocadherins, several genes involved in neuronal development, including SLITRK2, CSMD1, and VGF, and several genes of unknown function. Conclusions: A copy number variant (CNV) that confers risk for strabismus affects gene expression of several genes involved in neural development, highlighting that strabismus most likely results from abnormal neural development, and identifying several new genes and pathways for further research into the pathophysiology of strabismus. Full article

(This article belongs to the Special Issue Genetics of Eye Development and Diseases)

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19 pages, 6027 KB

Open AccessEditor’s ChoiceArticle

The X-Linked Tumor Suppressor TSPX Regulates Genes Involved in the EGFR Signaling Pathway and Cell Viability to Suppress Lung Adenocarcinoma

by Tatsuo Kido, Hui Kong and Yun-Fai Chris Lau

Genes 2025, 16(1), 75; https://doi.org/10.3390/genes16010075 - 11 Jan 2025

Cited by 2 | Viewed by 1609

Abstract

Background: TSPX is an X-linked tumor suppressor that was initially identified in non-small cell lung cancer (NSCLC) cell lines. However, its expression patterns and downstream mechanisms in NSCLC remain unclear. This study aims to investigate the functions of TSPX in NSCLC by identifying [...] Read more.

Background: TSPX is an X-linked tumor suppressor that was initially identified in non-small cell lung cancer (NSCLC) cell lines. However, its expression patterns and downstream mechanisms in NSCLC remain unclear. This study aims to investigate the functions of TSPX in NSCLC by identifying its potential downstream targets and their correlation with clinical outcomes. Methods: RNA-seq transcriptome and pathway enrichment analyses were conducted on the TSPX-overexpressing NSCLC cell lines, A549 and SK-MES-1, originating from lung adenocarcinoma and squamous cell carcinoma subtypes, respectively. In addition, comparative analyses were performed using the data from clinical NSCLC specimens (515 lung adenocarcinomas and 502 lung squamous cell carcinomas) in the Cancer Genome Atlas (TCGA) database. Results: TCGA data analysis revealed significant downregulation of TSPX in NSCLC tumors compared to adjacent non-cancerous tissues (Wilcoxon matched pairs signed rank test p < 0.0001). Notably, the TSPX expression levels were inversely correlated with the cancer stage, and higher TSPX levels were associated with better clinical outcomes and improved survival in lung adenocarcinoma, a subtype of NSCLC (median survival extended by 510 days; log-rank test, p = 0.0025). RNA-seq analysis of the TSPX-overexpressing NSCLC cell lines revealed that TSPX regulates various genes involved in the cancer-related signaling pathways and cell viability, consistent with the suppression of cell proliferation in cell culture assays. Notably, various potential downstream targets of TSPX that correlated with patient survival (log-rank test, p = 0.016 to 4.3 × 10⁻¹⁰) were identified, including EGFR pathway-related genes AREG, EREG, FOSL1, and MYC, which were downregulated. Conclusions: Our results suggest that TSPX plays a critical role in suppressing NSCLC progression by downregulating pro-oncogenic genes, particularly those in the EGFR signaling pathway, and upregulating the tumor suppressors, especially in lung adenocarcinoma. These findings suggest that TSPX is a potential biomarker and therapeutic target for NSCLC management. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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11 pages, 634 KB

Open AccessEditor’s ChoiceArticle

The Impact of Storage Conditions on DNA Preservation in Human Skeletal Remains: A Comparison of Freshly Excavated Samples and Those Stored for 12 Years in a Museum Depot

by Tonja Jeromelj, Tamara Leskovar and Irena Zupanič Pajnič

Genes 2025, 16(1), 78; https://doi.org/10.3390/genes16010078 - 11 Jan 2025

Cited by 3 | Viewed by 4169

Abstract

Background: As the field of ancient DNA research continues to evolve and produce significant discoveries, it is important to address the crucial limitations it still faces. Under conducive conditions, DNA can persist for thousands of years within human skeletal remains, but, as excavation [...] Read more.

Background: As the field of ancient DNA research continues to evolve and produce significant discoveries, it is important to address the crucial limitations it still faces. Under conducive conditions, DNA can persist for thousands of years within human skeletal remains, but, as excavation occurs, the environment abruptly changes, often leading to the loss of DNA and valuable genetic information. Proper storage procedures are needed to mediate DNA degradation and maintain sample integrity. This study aimed to investigate the impact of long-term storage under unregulated temperatures and humidity conditions on DNA preservation in human skeletal remains. Methods: To achieve this, archaeological petrous bones were used for DNA recovery. The DNA yield and degree of DNA degradation were compared for samples originating from historically and geographically equivalent archaeological sites, which differed in times of excavation and, consequently, in storage durations and conditions. DNA yield and the degree of DNA degradation were determined using real time PCR. Results: A significant reduction in the DNA yield and a borderline significant increase in the degree of DNA degradation were detected for samples stored at unregulated conditions for approximately 12 years. Conclusions: Our results show the imperative need for adhering to scientific recommendations regarding the optimal temperature and humidity in the long-term storage of human skeletal material. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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14 pages, 2318 KB

Open AccessEditor’s ChoiceReview

Hypertrophic Cardiomyopathy: New Clinical and Therapeutic Perspectives of an “Old” Genetic Myocardial Disease

by Chiara Calore, Mario Mangia, Cristina Basso, Domenico Corrado and Gaetano Thiene

Genes 2025, 16(1), 74; https://doi.org/10.3390/genes16010074 - 10 Jan 2025

Cited by 3 | Viewed by 4359

Abstract

Since its first pathological description over 65 years ago, hypertrophic cardiomyopathy (HCM), with a worldwide prevalence of 1:500, has emerged as the most common genetically determined cardiac disease. Diagnostic work-up has dramatically improved over the last decades, from clinical suspicion and abnormal electrocardiographic [...] Read more.

Since its first pathological description over 65 years ago, hypertrophic cardiomyopathy (HCM), with a worldwide prevalence of 1:500, has emerged as the most common genetically determined cardiac disease. Diagnostic work-up has dramatically improved over the last decades, from clinical suspicion and abnormal electrocardiographic findings to hemodynamic studies, echocardiography, contrast-enhanced cardiac magnetic resonance, and genetic testing. The implementation of screening programs and the use of implantable cardioverter defibrillators (ICDs) for high-risk individuals have notably reduced arrhythmic sudden deaths, altering the disease’s mortality profile. Therapeutic breakthroughs, including surgical myectomy, alcohol septal ablation, and the novel introduction of “myosin inhibitors”, have revolutionized symptom management and reduced progression to advanced heart failure (HF) and death. Despite this progress, refractory HF—both with preserved and reduced systolic function—has become the predominant cause of HCM-related mortality. While most patients with HCM experience a favorable clinical course with low morbidity and mortality, timely identification and targeted treatment of high-risk subgroups progressing toward progressive HF remain a pressing challenge, even for expert clinicians. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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