Genes

19 pages, 8965 KiB

Open AccessArticle

Oxidative Stress and Intestinal Transcriptome Changes in Clostridium perfringens Type A-Caused Enteritis in Deer

by Meihui Wang, Qingyun Guo, Zhenyu Zhong, Qingxun Zhang, Yunfang Shan, Zhibin Cheng, Xiao Wang, Yuping Meng, Yulan Dong and Jiade Bai

Genes 2025, 16(8), 949; https://doi.org/10.3390/genes16080949 - 11 Aug 2025

Abstract

Background: Clostridium perfringens (C. perfringens) type A is a major cause of enteritis in farmed and wild deer populations, leading to significant economic losses in the deer industry. This bacterium produces toxins that damage the intestine. Methods: In this [...] Read more.

Background: Clostridium perfringens (C. perfringens) type A is a major cause of enteritis in farmed and wild deer populations, leading to significant economic losses in the deer industry. This bacterium produces toxins that damage the intestine. Methods: In this study, we performed transcriptome analysis by establishing an intestinal circulation model of the intestines of fallow deer (Dama Dama) inoculated with C. perfringens type A versus those not inoculated with C. perfringens type A. In a further step, we determined the protein content of immunoinflammation-related molecules by ELISA and the antioxidant capacity of the intestine to investigate the molecular mechanisms of C. perfringens type A-induced enteritis. Results: Transcriptome analysis revealed significant enrichment of pathways related to the haematopoietic system, oxidative stress, the immune system and intestinal tight junctions. Additionally, C. perfringens α-toxin enters the intestine and may be recognized by TLR6, activating the immune system, increasing the secretion of various cytokines and inflammasome components, inducing oxidative stress and damaging the intestine. Conclusions: This study provides a comprehensive transcriptomic basis for understanding the selective differential expression of genes in deer enteritis induced by C. perfringens type A and provides a broader guide for finding therapeutic approaches to deer enteritis. Full article

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

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Graphical abstract

22 pages, 1122 KiB

Open AccessReview

Muscle Aging Heterogeneity: Genetic and Structural Basis of Sarcopenia Resistance

by Angelina Titova, Airat Bilyalov, Nikita Filatov, Stepan Perepechenov, Darya Kupriyanova, Sergei Brovkin, Dmitrii Shestakov, Natalia Bodunova and Oleg Gusev

Genes 2025, 16(8), 948; https://doi.org/10.3390/genes16080948 - 11 Aug 2025

Abstract

Sarcopenia, the progressive loss of skeletal muscle mass and function with age, significantly contributes to frailty and mortality in older adults. Notably, muscles do not age uniformly—some retain structure and strength well into old age. This review explores the mechanisms underlying differential resistance [...] Read more.

Sarcopenia, the progressive loss of skeletal muscle mass and function with age, significantly contributes to frailty and mortality in older adults. Notably, muscles do not age uniformly—some retain structure and strength well into old age. This review explores the mechanisms underlying differential resistance to muscle aging, with a focus on sarcopenia-resistant muscles. We analyzed current literature across molecular biology, genetics, and physiology to identify key regulators of muscle preservation during aging. Special attention was given to muscle fiber types, mitochondrial function, neuromuscular junctions, and satellite cell activity. Muscles dominated by slow-twitch (type I) fibers—such as the soleus, diaphragm, and extraocular muscles—demonstrate enhanced resistance to sarcopenia. This resilience is linked to sustained oxidative metabolism, high mitochondrial density, robust antioxidant defenses, and preserved regenerative capacity. Key molecular pathways include mTOR, PGC-1α, and SIRT1/6, while genetic variants in ACTN3, MSTN, and FOXO3 contribute to interindividual differences. In contrast, fast-twitch muscles are more vulnerable due to lower oxidative capacity and satellite cell depletion. Unique innervation patterns and neurotrophic support further protect muscles like extraocular muscles from age-related atrophy. Resistance to sarcopenia is driven by a complex interplay of intrinsic and extrinsic factors. Understanding why specific muscles age more slowly provides insights into muscle resilience and suggests novel strategies for targeted prevention and therapy. Expanding research beyond traditionally studied muscles is essential to develop comprehensive interventions to preserve mobility and independence in aging populations. Full article

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

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18 pages, 10372 KiB

Open AccessArticle

Alternative Splicing of Serum Response Factor Reveals Isoform-Specific Remodeling in Cardiac Diseases

by Sayed Aliul Hasan Abdi, Gohar Azhar, Xiaomin Zhang, Shakshi Sharma, Mohib Hafeez and Jeanne Y. Wei

Genes 2025, 16(8), 947; https://doi.org/10.3390/genes16080947 - 11 Aug 2025

Abstract

Background: Alternative splicing is an important mechanism of transcriptomic and proteomic diversity and is progressively involved in cardiovascular disease (CVD) pathogenesis. Serum response factor (SRF), a critical transcription factor in cardiac development and function, may itself undergo splicing regulation, potentially altering its function [...] Read more.

Background: Alternative splicing is an important mechanism of transcriptomic and proteomic diversity and is progressively involved in cardiovascular disease (CVD) pathogenesis. Serum response factor (SRF), a critical transcription factor in cardiac development and function, may itself undergo splicing regulation, potentially altering its function in disease states. Objective: The objective of this study is to identify SRF-associated alternative splicing events in cardiac pathological conditions and examine regulatory interactions with splicing factors using RNA-seq data. Methods: Three human heart RNA-seq databases (PRJNA198165, PRJNA477855, PRJNA678360) were used, comprising various cardiac conditions like non-ischemic cardiomyopathy (NICM), ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), and heart failure with reduced ejection fraction (HFrEF), with and without left ventricular assist device (LVAD) support. Splicing events were identified using the rMATS tool, and correlation analyses were performed between SRF and predicted splicing factors. Functional enrichment of SRF-correlated genes was assessed via Gene Ontology (GO) and KEGG pathways. Results: The skipped exon (SE) events were the predominant splicing type across all datasets. SRF chr6, including (Exon 2, 43,173,847–43,174,113), (Exon 4, 43,176,548–43,176,667), and (Exon 5, 43,178,294-43,178,485), were most frequently involved in SE and mutually exclusive exon (MXE) events across multiple heart failure subtypes. Correlation analysis revealed strong positive associations between SRF and several splicing factors (HNRNPL, HNRNPD, SRSF5, and SRSF8). GO and KEGG analyses revealed enrichment of muscle development, sarcomere structure, lipid metabolism, and immune signaling pathways. Conclusions: Our study shows that SRF is subject to extensive alternative splicing in heart failure, particularly at Exon 2 and Exon 5, suggesting isoform-specific roles in cardiac remodeling. The strong co-expression with specific splicing factors delineates a regulatory axis that may explain the pathological transcriptome in cardiomyopathy. These findings provide a foundation for exploring splicing-based biomarkers and therapeutic targets in cardiac pathology for SRF. Full article

(This article belongs to the Special Issue Advances in Bioinformatics of Human Diseases)

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18 pages, 1326 KiB

Open AccessArticle

Exploring the Functional Potential of the Broiler Gut Microbiome Using Shotgun Metagenomics

by Nuria Peña, Irene Lafuente, Ester Sevillano, Javier Feito, Gastón Allendez, Estefanía Muñoz-Atienza, Fiona Crispie, Luis M. Cintas, Paul D. Cotter, Pablo E. Hernández and Juan Borrero

Genes 2025, 16(8), 946; https://doi.org/10.3390/genes16080946 - 11 Aug 2025

Abstract

Background/Objectives: Antimicrobial peptides (AMPs) have emerged as promising alternatives to conventional antibiotics in livestock, offering a sustainable strategy for controlling bacterial pathogens in food production systems. In addition to their direct antimicrobial effects, AMPs play a key role in modulating host-associated microbiomes, [...] Read more.

Background/Objectives: Antimicrobial peptides (AMPs) have emerged as promising alternatives to conventional antibiotics in livestock, offering a sustainable strategy for controlling bacterial pathogens in food production systems. In addition to their direct antimicrobial effects, AMPs play a key role in modulating host-associated microbiomes, influencing both microbial composition and function. Advances in metagenomic sequencing and bioinformatic tools now enable comprehensive exploration of AMP diversity and activity within complex microbial ecosystems. Methods: In this study, we employed Illumina-based next-generation sequencing (NGS) to analyze intestinal contents from six gut sections of broiler chickens obtained from a Spanish slaughterhouse. Results: Through de novo assembly and bioinformatic annotation, we identified biosynthetic gene clusters (BGCs) encoding ribosomally synthesized and post-translationally modified peptides (RiPPs), other specialized bioactive secondary metabolites, antimicrobial resistance genes (ARGs), virulence factor genes (VFGs), and a diverse microbial community. Among all gut sections, the cecum exhibited the highest genetic richness, characterized by a high diversity of RiPP-like clusters and antimicrobial resistance determinants. Conclusions: These findings highlight the poultry gut, particularly the cecum, as a significant reservoir of antimicrobial peptides (AMPs) with potential implications in antibiotic-free poultry production and enhanced food safety. Full article

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

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19 pages, 5625 KiB

Open AccessArticle

Genome-Wide Association Study and Meta-Analysis Uncovers Key Candidate Genes for Body Weight Traits in Chickens

by Jintian Wen, Ming Zheng, Zhaochuan Wang, Xiaoxiang Hu and Zhenhui Li

Genes 2025, 16(8), 945; https://doi.org/10.3390/genes16080945 - 11 Aug 2025

Abstract

Background: Genome-wide association studies (GWAS) have been extensively employed to elucidate the genetic architecture of body weight (BW) traits in chickens, which represent key economic indicators in broiler production. With the growing availability of genomic data from diverse commercial and resource chicken populations, [...] Read more.

Background: Genome-wide association studies (GWAS) have been extensively employed to elucidate the genetic architecture of body weight (BW) traits in chickens, which represent key economic indicators in broiler production. With the growing availability of genomic data from diverse commercial and resource chicken populations, a critical challenge lies in how to effectively integrate these datasets to enhance sample size and thereby improve the statistical power for detecting genetic variants associated with complex traits. Methods: In this study, we performed a multi-population GWAS meta-analysis on BW traits across three genetically distinct chicken populations, focusing on BW at 56, 70, and 84 days of age: P1 (N301 Yellow Plumage Dwarf Chicken Line; n = 426), P2 (F2 reciprocal cross: High Quality Line A × Huiyang Bearded chicken; n = 494), and P3 (F2 cross: Black-bone chicken × White Plymouth Rock; n = 223). Results: Compared to single-population GWAS, our meta-analysis identified 77 novel independent variants significantly associated with BW traits, while gene-based association analysis implicated 59 relevant candidate genes. Functional annotation of BW56- and BW84-associated SNPs (single-nucleotide polymorphisms) 1_170526144G>T and 1_170642110A>G, integrated with tissue-specific regulatory annotations, revealed significant enrichment of enhancer and promoter elements for KPNA3 and CAB39L in muscle, adipose, and intestinal tissues. Through this meta-analysis and integrative genomics approach, we identified novel candidate genes associated with body weight traits in chickens. Conclusions: These findings provide valuable mechanistic insights into the genetic mechanisms underlying body weight regulation in poultry and offer important references for selective breeding strategies aimed at improving production efficiency in the poultry industry. Full article

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

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13 pages, 1056 KiB

Open AccessArticle

Genetic Panel Testing for Malignant Hyperthermia in Japan: Discovery of Novel Variants and Clinical Implications

by Hirotsugu Miyoshi, Keiko Mukaida, Sachiko Otsuki, Kenshiro Kido, Ayako Sumii, Tsuyoshi Ikeda, Guoqiang Xia, Yuko Noda, Tomomi Ishii, Satoshi Kamiya, Soshi Narasaki, Hiroshi Niinai and Yasuo M. Tsutsumi

Genes 2025, 16(8), 944; https://doi.org/10.3390/genes16080944 - 11 Aug 2025

Abstract

Background: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle triggered by certain anesthetic agents. While Ryanodine Receptor 1 (RYR1) and Calcium Voltage-Gated Channel Subunit Alpha1 S (CACNA1S) are well-established susceptibility genes, the complete genetic basis of MH [...] Read more.

Background: Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle triggered by certain anesthetic agents. While Ryanodine Receptor 1 (RYR1) and Calcium Voltage-Gated Channel Subunit Alpha1 S (CACNA1S) are well-established susceptibility genes, the complete genetic basis of MH remains unclear, particularly in Asian populations. Methods: We conducted gene panel testing targeting 24 calcium-related genes in 338 individuals from 247 Japanese families with suspected or confirmed MH. Variants were analyzed on a gene-by-gene basis, and their pathogenicity was assessed using in silico prediction tools. Additionally, patients were classified into subgroups based on the results of the calcium-induced calcium release (CICR) assay and the Clinical Grading Scale (CGS) score. Results: Candidate pathogenic variants were identified in 118 families (48.2%), including 73 (29.8%) in RYR1, 16 (6.5%) in CACNA1S, and 62 (25.3%) in other genes. Among CICR-positive families, RYR1 and CACNA1S variants were detected in 42.0% and 5.3% of cases, respectively. In individuals with high CGS scores (Ranks 5–6), RYR1 and CACNA1S variants were observed in 56.0% and 12.0%, respectively. Variants in other genes such as STAC3, CASQ1, ATP2A1, ASPH, HRC and TRPV1 were also detected. Conclusions: Our findings confirm the predominant role of RYR1 and CACNA1S in MH susceptibility in the Japanese population and highlight additional candidate genes that may contribute to the condition. Broader genetic screening and functional validation studies are warranted to further elucidate the polygenic nature of MH. Full article

(This article belongs to the Section Genetic Diagnosis)

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15 pages, 584 KiB

Open AccessReview

MicroRNAs as Potential Biomarkers for Alzheimer’s Disease in Women

by Shiwei Huang, Lily Zhong, Lilly Zheng and Jian Shi

Genes 2025, 16(8), 943; https://doi.org/10.3390/genes16080943 - 11 Aug 2025

Abstract

Alzheimer’s disease (AD) affects approximately 50 million people worldwide, with women comprising two-thirds of those affected. Despite this disproportionate impact, the sex-specific pathological mechanisms underlying AD in women remain poorly understood, and female-specific biomarkers have been significantly understudied. This critical knowledge gap requires [...] Read more.

Alzheimer’s disease (AD) affects approximately 50 million people worldwide, with women comprising two-thirds of those affected. Despite this disproportionate impact, the sex-specific pathological mechanisms underlying AD in women remain poorly understood, and female-specific biomarkers have been significantly understudied. This critical knowledge gap requires focused research to improve diagnostic and therapeutic approaches for women with AD. In this review, we systematically examine the pathological mechanisms underlying AD in women, including sex-related differences in inflammation, autophagy, and metabolic dysfunction. We further explore microRNA (miRNA) expression patterns and evaluate miRNA candidates as potential biomarkers for AD in women based on current literature. Through this analysis, we identified approximately 20 miRNA candidates derived from diverse human samples, including brain tissue, blood, and cerebrospinal fluid, in multiple independent studies. These candidates demonstrate the potential for developing accessible, non-invasive biomarkers, particularly those identified in blood and cerebrospinal fluid. However, the limited overlap between studies highlights that female-specific miRNA biomarker research for AD remains in its early discovery phase, emphasizing the urgent need for large-scale validation studies and standardized methodological approaches to advance this promising field for clinical application. Full article

(This article belongs to the Special Issue Unraveling the Complex Role of Non-Coding RNAs in Neurodegenerative Diseases)

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12 pages, 1773 KiB

Open AccessBrief Report

Effects of Aging on Z-DNA-Induced Genetic Instability In Vivo

by Tonia T. Li, Alexandra D’Amico, Laura Christensen and Karen M. Vasquez

Genes 2025, 16(8), 942; https://doi.org/10.3390/genes16080942 - 11 Aug 2025

Abstract

Repetitive DNA sequences are abundant in genomes and can adopt alternative DNA structures (i.e., non-B DNA). One such structure, Z-DNA, has been shown to stimulate genetic instability in a variety of organisms, including human cells and mice. Z-DNA-forming sequences are enriched at mutation [...] Read more.

Repetitive DNA sequences are abundant in genomes and can adopt alternative DNA structures (i.e., non-B DNA). One such structure, Z-DNA, has been shown to stimulate genetic instability in a variety of organisms, including human cells and mice. Z-DNA-forming sequences are enriched at mutation hotspots in human cancer genomes, implicating them in cancer etiology. Aging is a known risk factor for the development of cancer, and genetic instability is a hallmark of both aging and cancer. However, how aging affects the mutagenic potential of Z-DNA has not yet been investigated. Here, we explored the effects of aging on the mutagenic processing of Z-DNA using a transgenic mouse model. Surprisingly, Z-DNA-induced mutations decreased or remained unchanged with increasing age. Cleavage of Z-DNA was unaffected with increasing age, suggesting that downstream repair processing, such as double-strand break repair processes, may be involved in the age-related changes in Z-DNA-induced mutagenesis in mice. Full article

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

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19 pages, 1119 KiB

Open AccessArticle

Analysis of the Genetic Mechanism of Yield-Related Traits of Maize in Cold Regions

by Chao Gao, Zimeng Li, Guogang Zheng, Hong Di, Lin Zhang, Zhenhua Wang and Ling Dong

Genes 2025, 16(8), 941; https://doi.org/10.3390/genes16080941 - 8 Aug 2025

Abstract

Background: Maize is an important food crop in cold regions, especially in Northeast China. However, its short growth period and low-temperature stress pose challenges to the breeding of high-yield hybrids. With climate warming, the maize planting area continues to expand to high latitudes. [...] Read more.

Background: Maize is an important food crop in cold regions, especially in Northeast China. However, its short growth period and low-temperature stress pose challenges to the breeding of high-yield hybrids. With climate warming, the maize planting area continues to expand to high latitudes. Research on cold-region maize is of great significance to ensure food security and sustainable agricultural development. However, most of the current maize research is concentrated in temperate and tropical regions, and there are few studies on cold-region maize. Methods: Based on this, this study selected some representative cold-region maize materials and materials whose adaptability has not yet been verified, and used a semi-diallel hybrid design for hybridization to determine the general combining ability (GCA) and specific combining ability (SCA) to screen out excellent breeding materials suitable for cold regions. Field experiments were carried out under four different cold environments, and 55 hybrid progenies and their parents were evaluated. The double allele hybridization analysis based on the Griffing method 2 (model 1) showed that the specific combining ability (SCA) and general combining ability (GCA) effects of each trait were significant. Results: The GCA mean square of all traits except yield and number of grains per row was greater than the SCA mean square, indicating that additive gene effects were dominant and genetic improvement through selective breeding was feasible. Hayman plot analysis under four environments showed that yield, ear length, number of grains per row, water content, and plant height were mainly controlled by superdominant genes, while stem thickness, number of nodes, and ear position were controlled by some dominant genes. Conclusions: Parent P1 contained more recessive genes in yield traits, but more dominant genes in number of grains per row, number of nodes, and ear position; P3 contained more dominant genes in yield and water content, but more recessive genes in number of nodes and ear position; P7 contained more recessive genes in most traits; and P9 contained more dominant genes in most traits. P9 and P6 represent excellent parental germplasm, among which the hybrid combinations P1 × P9, P2 × P5, P3 × P10, P4 × P6, P5 × P8, P6 × P9, P7 × P10, and P8 × P10 all show hybrid vigor exceeding that of their parents and have high breeding value. Full article

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

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22 pages, 1682 KiB

Open AccessReview

Histone Modifications as Individual-Specific Epigenetic Regulators: Opportunities for Forensic Genetics and Postmortem Analysis

by Sheng Yang, Liqin Chen, Miaofang Lin, Chengwan Shen and Aikebaier Reheman

Genes 2025, 16(8), 940; https://doi.org/10.3390/genes16080940 - 7 Aug 2025

Abstract

Histone post-translational modifications (PTMs) have emerged as promising epigenetic biomarkers with increasing forensic relevance. Unlike conventional genetic markers such as short tandem repeats (STRs), histone modifications can offer additional layers of biological information, capturing individual-specific regulatory states and remaining detectable even in degraded [...] Read more.

Histone post-translational modifications (PTMs) have emerged as promising epigenetic biomarkers with increasing forensic relevance. Unlike conventional genetic markers such as short tandem repeats (STRs), histone modifications can offer additional layers of biological information, capturing individual-specific regulatory states and remaining detectable even in degraded forensic samples. This review highlights recent advances in understanding histone PTMs in forensic contexts, focusing on three key domains: analysis of degraded biological evidence, differentiation of monozygotic (MZ) twins, and postmortem interval (PMI) estimation. We summarize experimental findings from human cadavers, animal models, and typical forensic samples including bone, blood, and muscle, illustrating the stability and diagnostic potential of marks such as H3K4me3, H3K27me3, and γ-H2AX. Emerging technologies including CUT&Tag, MALDI imaging, and nanopore-based sequencing offer novel opportunities to profile histone modifications at high resolution and low input. Despite technical challenges, these findings support the feasibility of histone-based biomarkers as complementary tools for forensic identification and temporal analysis. Future work should prioritize methodological standardization, inter-laboratory validation, and integration into forensic workflows. However, the forensic applicability of these modifications remains largely unvalidated, and further studies are required to assess their reliability in casework contexts. Full article

(This article belongs to the Section Epigenomics)

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18 pages, 508 KiB

Open AccessReview

RNF213-Related Vasculopathy: An Entity with Diverse Phenotypic Expressions

by Takeshi Yoshimoto, Sho Okune, Shun Tanaka, Hiroshi Yamagami and Yuji Matsumaru

Genes 2025, 16(8), 939; https://doi.org/10.3390/genes16080939 - 7 Aug 2025

Abstract

Moyamoya disease (MMD) is primarily associated with genetic variants in RNF213. RNF213 p.R4810K (c.14429G>A, p.Arg4810Lys) is a founder variant predominantly found in East Asian populations and is strongly associated with MMD, a rare cerebrovascular condition characterized by progressive stenosis of intracranial arteries [...] Read more.

Moyamoya disease (MMD) is primarily associated with genetic variants in RNF213. RNF213 p.R4810K (c.14429G>A, p.Arg4810Lys) is a founder variant predominantly found in East Asian populations and is strongly associated with MMD, a rare cerebrovascular condition characterized by progressive stenosis of intracranial arteries and the development of abnormal collateral networks. Recent evidence suggests that RNF213 variants are also enriched in non-moyamoya intracranial arteriopathies, such as large-artery atherosclerotic stroke and intracranial arterial stenosis/occlusion (ICASO), particularly in east Asian individuals with early-onset or cryptogenic stroke. This expanded phenotypic spectrum, termed RNF213-related vasculopathy (RRV), represents a distinct pathogenic entity that may involve unique pathogenic processes separate from traditional atherosclerosis. In this review, we synthesize current genetic, clinical, radiological, and experimental findings that delineate the unique features of RRV. Patients with RRV typically exhibit a lower burden of traditional vascular risk factors, negative vascular remodeling in the absence of atheromatous plaques, and an increased propensity for disease progression. RNF213 variants may compromise vascular resilience by impairing adaptive responses to hemodynamic stress. Furthermore, emerging cellular and animal model data indicate that RNF213 influences angiogenesis, lipid metabolism, and stress responses, offering mechanistic insights into its role in maintaining vascular integrity. Recognizing RRV as a distinct clinical entity has important implications for diagnosis, risk stratification, and the development of genome-informed therapeutic strategies. Full article

(This article belongs to the Special Issue Genetic Research on Cerebrovascular Disease and Stroke)

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8 pages, 3739 KiB

Open AccessCommunication

Molecular Screening of Feline Glycogen Storage Disease Type II (Pompe Disease): Allele Frequencies of the GAA:c.1799G>A and c.55G>A Variants

by Abdullah Al Faruq, Tofazzal Md Rakib, Md Shafiqul Islam, Akira Yabuki, Shahnaj Pervin, Shinichiro Maki, Shigeki Tanaka, Nanami Arakawa and Osamu Yamato

Genes 2025, 16(8), 938; https://doi.org/10.3390/genes16080938 - 7 Aug 2025

Abstract

Background/Objectives: Glycogen storage disease type II, also known as Pompe disease (PD), is a rare autosomal recessive genetic disorder triggered by a deficiency in lysosomal acid α-glucosidase (GAA). Recently, we discovered two deleterious missense variants of the GAA gene, c.1799G>A (p.Arg600His) (a pathogenic [...] Read more.

Background/Objectives: Glycogen storage disease type II, also known as Pompe disease (PD), is a rare autosomal recessive genetic disorder triggered by a deficiency in lysosomal acid α-glucosidase (GAA). Recently, we discovered two deleterious missense variants of the GAA gene, c.1799G>A (p.Arg600His) (a pathogenic mutation) and c.55G>A (p.Val19Met), in a domestic short-haired cat with PD. This study aimed to design genotyping assays for these two variants and ascertain their allele frequencies in Japanese cat populations. Methods: We developed fluorescent probe-based real-time polymerase chain reaction assays to genotype the c.1799G>A and c.55G>A variants. A total of 738 cats, comprising 99 purebred cats from 20 breeds and 540 mixed-breed cats, were screened using these assays. Results: Genotyping assays clearly differentiated all known genotypes of the two variants. None of the 738 cats tested carried the c.1799G>A variant. However, we identified cats with c.55G/A and c.55A/A genotypes in the purebred (A allele frequency: 0.081) and mixed-breed cats (0.473). A significant difference (p < 0.001) was observed in the A allele frequency between the two groups. Conclusions: The c.1799G>A mutation appears rare in cat populations, suggesting it may be confined to specific pedigree Japanese mixed-breed cats. The c.55G>A variant was detected in purebred and mixed-breed cats, suggesting that it may not be directly linked to feline PD. However, additional studies are required to elucidate the precise relationship between this variant and cardiac function. Genotyping assays will serve as valuable tools for diagnosing and genotyping feline PD. Full article

(This article belongs to the Special Issue Hereditary Traits and Diseases in Companion Animals)

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10 pages, 902 KiB

Open AccessCase Report

Gene Mutation-Negative Malignant Melanoma in a Prepubertal Patient: A Clinical and Molecular Case Report

by Adrian Guźniczak, Patrycja Sosnowska-Sienkiewicz, Jarosław Szydłowski, Paweł Kurzawa and Danuta Januszkiewicz-Lewandowska

Genes 2025, 16(8), 937; https://doi.org/10.3390/genes16080937 - 6 Aug 2025

Abstract

Conventional melanoma is exceedingly rare in the pediatric population, particularly among prepubescent children, and its diagnosis and management necessitate a multidisciplinary approach. The objective of this present report is to delineate the diagnostic pathway and therapeutic management of a 4-year-old girl with conventional [...] Read more.

Conventional melanoma is exceedingly rare in the pediatric population, particularly among prepubescent children, and its diagnosis and management necessitate a multidisciplinary approach. The objective of this present report is to delineate the diagnostic pathway and therapeutic management of a 4-year-old girl with conventional melanoma, with particular focus on the molecular context. A pigmented lesion located on the auricle was surgically excised, and subsequent histopathological and immunohistochemical analyses confirmed the diagnosis of malignant melanoma (pT3b). Radiologic investigations revealed no evidence of metastatic disease, and comprehensive genetic testing utilizing next-generation sequencing (NGS) identified no pathogenic variants in the germline genes examined, nor in the BRAF, NRAS, KRAS, and TP53 genes within the excised lesion. The patient remains in good general health. This case report adds to the limited body of literature on melanoma in pediatric patients and underscores the importance of thorough diagnostic evaluation in this age group. Full article

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

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25 pages, 3822 KiB

Open AccessArticle

Comparative Transcriptome and MicroRNA Profiles of Equine Mesenchymal Stem Cells, Fibroblasts, and Their Extracellular Vesicles

by Sebastian Sawicki, Monika Bugno-Poniewierska, Jakub Żurowski, Tomasz Szmatoła, Ewelina Semik-Gurgul, Michał Bochenek, Elżbieta Karnas and Artur Gurgul

Genes 2025, 16(8), 936; https://doi.org/10.3390/genes16080936 - 5 Aug 2025

Abstract

Background: Mesenchymal stem cells (MSCs) are a promising tool in regenerative medicine due to their ability to secrete paracrine factors that modulate tissue repair. Extracellular vesicles (EVs) released by MSCs contain bioactive molecules (e.g., mRNAs, miRNAs, proteins) and play a key role in [...] Read more.

Background: Mesenchymal stem cells (MSCs) are a promising tool in regenerative medicine due to their ability to secrete paracrine factors that modulate tissue repair. Extracellular vesicles (EVs) released by MSCs contain bioactive molecules (e.g., mRNAs, miRNAs, proteins) and play a key role in intercellular communication. Methods: This study compared the transcriptomic profiles (mRNA and miRNA) of equine MSCs derived from adipose tissue (AT-MSCs), bone marrow (BM-MSCs), and ovarian fibroblasts (as a differentiated control). Additionally, miRNAs present in EVs secreted by these cells were characterized using next-generation sequencing. Results: All cell types met ISCT criteria for MSCs, including CD90 expression, lack of MHC II, trilineage differentiation, and adherence. EVs were isolated using ultracentrifugation and validated with nanoparticle tracking analysis and flow cytometry (CD63, CD81). Differential expression analysis revealed distinct mRNA and miRNA profiles across cell types and their secreted EVs, correlating with tissue origin. BM-MSCs showed unique regulation of genes linked to early development and osteogenesis. EVs contained diverse RNA species, including miRNA, mRNA, lncRNA, rRNA, and others. In total, 227 and 256 mature miRNAs were detected in BM-MSCs and AT-MSCs, respectively, including two novel miRNAs per MSC type. Fibroblasts expressed 209 mature miRNAs, including one novel miRNA also found in MSCs. Compared to fibroblasts, 60 and 92 differentially expressed miRNAs were identified in AT-MSCs and BM-MSCs, respectively. Conclusions: The results indicate that MSC tissue origin influences both transcriptomic profiles and EV miRNA content, which may help to interpret their therapeutic potential. Identifying key mRNAs and miRNAs could aid in future optimizing of MSC-based therapies in horses. Full article

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

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11 pages, 260 KiB

Open AccessArticle

The Association of the COL27A1 rs946053 and TNC rs2104772s with Tendinopathies: A Case–Control Study in High-Level Croatian Athletes

by Goran Vrgoč, Saša Janković, Damir Knjaz, Ivana Duvnjak Orešković, Gordan Lauc and Nina Šimunić-Briški

Genes 2025, 16(8), 935; https://doi.org/10.3390/genes16080935 - 4 Aug 2025

Abstract

Background/Objectives: The increased risk of developing tendinopathies in athlete populations has led to investigations of several genes associated with tendon properties, suggesting that some individuals have a greater genetic predisposition for developing tendinopathies. The main purpose of this study was to investigate how [...] Read more.

Background/Objectives: The increased risk of developing tendinopathies in athlete populations has led to investigations of several genes associated with tendon properties, suggesting that some individuals have a greater genetic predisposition for developing tendinopathies. The main purpose of this study was to investigate how the functional polymorphisms within the COL5A1, COL27A1 and TNC genes impact the risk of developing tendinopathies in high-level Croatian athletes. Methods: For this case–control genetic study, we recruited 63 high-level athletes with a diagnosis of tendinopathies and 92 healthy asymptomatic individuals as controls. All individuals were genotyped for three single-nucleotide polymorphisms (SNPs) within the COL5A1, COL27A1 and TNC genes using the pyrosequencing method. Results: TNC rs2104772 TT (p = 0.0089) and the T-T-T haplotype (p = 0.0234), constructed from rs12722, rs946053 and rs2104772, were significantly overrepresented in cases versus controls, implicating a predisposition for tendinopathies. COL27A1 rs946053 GG (p = 0.0118) and the G-A-C haplotype (p = 0.0424), constructed from rs12722, rs946053 and rs2104772, were significantly overrepresented in controls, implicating a protective role. Conclusions: These results further support associations between functional polymorphisms within the COL27A1 and TNC genes and the risk of tendinopathies in high-level athletes. Further research is needed to replicate these results in various populations and larger cohorts. Full article

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

11 pages, 1293 KiB

Open AccessArticle

RAB24 Missense Variant in Dogs with Cerebellar Ataxia

by Cleo Schwarz, Jan Wennemuth, Julien Guevar, Francesca Dörn, Vidhya Jagannathan and Tosso Leeb

Genes 2025, 16(8), 934; https://doi.org/10.3390/genes16080934 - 4 Aug 2025

Abstract

Hereditary ataxias are a highly heterogenous group of diseases characterized by loss of coordination. In this study, we investigated a family of random-bred dogs, in which two siblings were affected by a slowly progressive ataxia. They presented with clinical signs of progressive cerebellar [...] Read more.

Hereditary ataxias are a highly heterogenous group of diseases characterized by loss of coordination. In this study, we investigated a family of random-bred dogs, in which two siblings were affected by a slowly progressive ataxia. They presented with clinical signs of progressive cerebellar ataxia, hypermetria, and absent menace response. The MRI revealed generalized brain atrophy, reduced cortical demarcation, hypoplastic corpus callosum, and cerebellar folia thinning, highly suggestive of a neurodegenerative disorder. We sequenced the genomes of the two affected dogs and their unaffected parents. Filtering for protein-changing variants that had homozygous alternate genotypes in the affected dogs, heterozygous genotypes in the parents, and homozygous reference genotypes in 1576 control genomes yielded a single missense variant in the RAB24 gene, XM_038534663.1:c.239G>T or XP_038390591.1:p.(Gly80Val). Genotypes at this variant showed the expected co-segregation with the ataxia phenotype in the investigated family. The predicted amino acid affects the conserved RabF4 motif. Glycine-80 resides at the protein surface and the introduction of a hydrophobic isopropyl side chain of the mutant valine might impede solvent accessibility. Another missense variant in RAB24, p.Glu38Pro, was previously reported to cause a clinically similar form of cerebellar ataxia in Gordon Setters and Old English Sheepdogs. Taken together, the available data suggest that RAB24:p.Gly80Val represents the causal variant in the studied dogs. To the best of our knowledge, this is only the second report of a potentially pathogenic RAB24 variant in any species and further supports that RAB24 should be considered a candidate gene in human ataxia patients with unclear molecular etiology. Full article

(This article belongs to the Special Issue Hereditary Traits and Diseases in Companion Animals)

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10 pages, 2785 KiB

Open AccessArticle

Integration of Genome and Epigenetic Testing in the Diagnostic Evaluation of Developmental Delay: Differentiating Börjeson–Forssman–Lehmann (BFLS) and White–Kernohan (WHIKERS) Syndromes

by Keri Ramsey, Supraja Prakash, Jennifer Kerkhof, Bekim Sadikovic, Susan White, Marcus Naymik, Jennifer Sloan, Anna Bonfitto, Newell Belnap, Meredith Sanchez-Castillo, Wayne Jepsen, Matthew Huentelman, Saunder Bernes, Vinodh Narayanan and Shagun Kaur

Genes 2025, 16(8), 933; https://doi.org/10.3390/genes16080933 - 4 Aug 2025

Abstract

Background: More than 1500 genes are associated with developmental delay and intellectual disability, with variants in many of these genes contributing to a shared phenotype. The discovery of variants of uncertain significance (VUS) found in these genes during genetic testing can lead [...] Read more.

Background: More than 1500 genes are associated with developmental delay and intellectual disability, with variants in many of these genes contributing to a shared phenotype. The discovery of variants of uncertain significance (VUS) found in these genes during genetic testing can lead to ambiguity and further delay in diagnosis and medical management. Phenotyping, additional genetic testing, and functional studies can all add valuable information to help reclassify these variants. Here we demonstrate the clinical utility of epigenetic signatures in prioritizing variants of uncertain significance in genes associated with developmental delay (DD) and intellectual disability (ID). Methods: Genome sequencing was performed in a male with developmental delay. He was found to have VUSs in both PHF6 and DDB1 genes, linked with Börjeson–Forssman–Lehmann syndrome (BFLS) and White–Kernohan syndrome (WHIKERS), respectively. These two disorders share a similar phenotype but have distinct inheritance patterns and molecular pathogenic mechanisms. DNA methylation profiling (DNAm) of whole blood was performed using the clinically validated EpiSign assay. Results: The proband’s methylation profile demonstrated a strong correlation with the BFLS methylation signature, supporting the PHF6 variant as a likely cause of his neurodevelopmental disorder. Conclusions: Epigenetic testing for disorders with distinct methylation patterns can provide diagnostic utility when a patient presents with variants of uncertain significance in genes associated with developmental delay. Epigenetic signatures can also guide genetic counselling and family planning. Full article

(This article belongs to the Special Issue Genetics and Genomics of Heritable Pediatric Disorders)

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21 pages, 6621 KiB

Open AccessArticle

Genome-Wide Identification and Expression Pattern Analysis of the Late Embryogenesis Abundant (LEA) Family in Foxtail Millet (Setaria italica L.)

by Yingying Qin, Yiru Zhao, Xiaoyu Li, Ruifu Wang, Shuo Chang, Yu Zhang, Xuemei Ren and Hongying Li

Genes 2025, 16(8), 932; https://doi.org/10.3390/genes16080932 - 4 Aug 2025

Abstract

Background/Objectives: Late embryogenesis abundant (LEA) proteins regulate stress responses and contribute significantly to plant stress tolerance. As a model species for stress resistance studies, foxtail millet (Setaria italica) lacks comprehensive characterization of its LEA gene family. This study aimed to [...] Read more.

Background/Objectives: Late embryogenesis abundant (LEA) proteins regulate stress responses and contribute significantly to plant stress tolerance. As a model species for stress resistance studies, foxtail millet (Setaria italica) lacks comprehensive characterization of its LEA gene family. This study aimed to comprehensively identify SiLEA genes in foxtail millet and elucidate their functional roles and tissue-specific expression patterns. Methods: Genome-wide identification of SiLEA genes was conducted, followed by phylogenetic reconstruction, cis-acting element analysis of promoters, synteny analysis, and expression profiling. Results: Ninety-four SiLEA genes were identified and classified into nine structurally distinct subfamilies, which are unevenly distributed across all nine chromosomes. Phylogenetic analysis showed closer clustering of SiLEA genes with sorghum and rice orthologs than with Arabidopsis thaliana AtLEA genes. Synteny analysis indicated the LEA gene family expansion through tandem and segmental duplication. Promoter cis-element analysis linked SiLEA genes to plant growth regulation, stress responses, and hormone signaling. Transcriptome analysis revealed tissue-specific expression patterns among SiLEA members, while RT-qPCR verified ABA-induced transcriptional regulation of SiLEA genes. Conclusions: This study identified 94 SiLEA genes grouped into nine subfamilies with distinct spatial expression profiles. ABA treatment notably upregulated SiASR-2, SiASR-5, and SiASR-6 in both shoots and roots. Full article

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

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22 pages, 5939 KiB

Open AccessArticle

Single-Nucleus Transcriptome Sequencing Unravels Physiological Differences in Holstein Cows Under Different Physiological States

by Peipei Li, Yaqiang Guo, Yanchun Bao, Caixia Shi, Lin Zhu, Mingjuan Gu, Risu Na and Wenguang Zhang

Genes 2025, 16(8), 931; https://doi.org/10.3390/genes16080931 - 3 Aug 2025

Abstract

Background: Against the backdrop of the large-scale and intensive development of the livestock industry, enhancing the reproductive efficiency of cattle has become a crucial factor in industrial development. Holstein cows, as the most predominant dairy cattle breed globally, are characterized by high milk [...] Read more.

Background: Against the backdrop of the large-scale and intensive development of the livestock industry, enhancing the reproductive efficiency of cattle has become a crucial factor in industrial development. Holstein cows, as the most predominant dairy cattle breed globally, are characterized by high milk yield and excellent milk quality. However, their reproductive efficiency is comprehensively influenced by a variety of complex factors, and improving their reproductive performance faces numerous challenges. The ovary, as the core organ of the female reproductive system, plays a decisive role in embryonic development and pregnancy maintenance. It is not only the site where eggs are produced and developed but it also regulates the cow’s estrous cycle, ovulation process, and the establishment and maintenance of pregnancy by secreting various hormones. The normal functioning of the ovary is crucial for the smooth development of the embryo and the successful maintenance of pregnancy. Methods: Currently, traditional sequencing technologies have obvious limitations in deciphering ovarian function and reproductive regulatory mechanisms. To overcome the bottlenecks of traditional sequencing technologies, this study selected Holstein cows as the research subjects. Ovarian samples were collected from one pregnant and one non-pregnant Holstein cow, and single-nucleus transcriptome sequencing technology was used to conduct an in-depth study on the ovarian cells of Holstein cows. Results: By constructing a cell type-specific molecular atlas of the ovaries, nine different cell types were successfully identified. This study compared the proportions of ovarian cell types under different physiological states and found that the proportion of endothelial cells decreased during pregnancy, while the proportions of granulosa cells and luteal cells increased significantly. In terms of functional enrichment analysis, oocytes during both pregnancy and non-pregnancy play roles in the “cell cycle” and “homologous recombination” pathways. However, non-pregnant oocytes are also involved in the “progesterone-mediated oocyte maturation” pathway. Luteal cells during pregnancy mainly function in the “cortisol synthesis and secretion” and “ovarian steroidogenesis” pathways; non-pregnant luteal cells are mainly enriched in pathway processes such as the “AMPK signaling pathway”, “pyrimidine metabolism”, and “nucleotide metabolism”. Cell communication analysis reveals that there are 51 signaling pathways involved in the pregnant ovary, with endothelial cells, granulosa cells, and luteal cells serving as the core communication hubs. In the non-pregnant ovary, there are 48 pathways, and the interaction between endothelial cells and stromal cells is the dominant mode. Conclusions: This study provides new insights into the regulatory mechanisms of reproductive efficiency in Holstein cows. The differences in the proportions of ovarian cell types, functional pathways, and cell communication patterns under different physiological states, especially the increase in the proportions of granulosa cells and luteal cells during pregnancy and the specificity of related functional pathways, indicate that these cells play a crucial role in the reproductive process of cows. These findings also highlight the importance of ovarian cells in pathways such as “cell cycle”, “homologous recombination”, and “progesterone-mediated oocyte maturation”, as well as the cell communication mechanisms in regulating ovarian function and reproductive performance. Full article

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

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