Search Results (108)

Background and Clinical Significance: Methyltransferase-like protein 5 (METTL5) is a conserved RNA methyltransferase responsible for catalyzing the N6-methyladenosine (m6A) modification of 18S ribosomal RNA, a process critical for ribosome biogenesis and translational regulation. Biallelic variants in METTL5 have been linked to autosomal recessive intellectual developmental disorder-72 (MRT72), typically presenting with microcephaly, intellectual disability, and speech delay. However, the association between METTL5 and isolated attention-deficit/hyperactivity disorder (ADHD) remains underexplored. Case Presentation: We report a 14-year-old Qatari female, born to consanguineous parents, who presented with microcephaly, speech delay, learning difficulties, and inattentive-type ADHD. Trio-based whole-genome sequencing identified a novel homozygous METTL5 variant (c.617G > A; p. Arg206Gln), with both parent’s heterozygous carriers. The variant is extremely rare (gnomAD MAF: 0.0000175) and predicted to be deleterious (CADD: 23.7; SIFT: damaging; PolyPhen-2: probably damaging). Structural modeling localized the change within the SAM-dependent catalytic domain, predicting protein destabilization (ΔΔG = +1.8 kcal/mol). The affected residue is highly conserved (ConSurf score: 8), and protein–protein interaction analysis linked METTL5 with METTL14, METTL16, and ZCCHC4, key regulators of rRNA methylation. Conclusions: In silico evidence suggests that the p. Arg206Gln variant disrupts METTL5 function, likely contributing to the observed neurodevelopmental phenotype, including ADHD. This expands the clinical spectrum of METTL5-related disorders and supports its inclusion in neurodevelopmental gene panels. Full article

Background: Pathogenic variants in interphotoreceptor matrix proteoglycan 1 (IMPG1) have been associated with autosomal dominant and recessive retinitis pigmentosa (RP) and autosomal dominant adult vitelliform macular dystrophy (AVMD). Monoallelic pathogenic variants in IMPG2 have been linked to maculopathy and biallelic variants to RP with early onset macular atrophy. Herein we characterise the phenotypic and genotypic features of patients with IMPG1/IMPG2 retinopathy and report novel variants. Methods: Patients with IMPG1 and IMPG2 variants and compatible phenotypes were retrospectively identified. Clinical data were obtained from reviewing the medical records. Phenotypic data included visual acuity, imaging included ultra-widefield pseudo-colour, fundus autofluorescence, and optical coherence tomography (OCT). Genetic testing was performed using next generation sequencing (NGS). Variant pathogenicity was investigated using in silico analysis (SIFT, PolyPhen-2, mutation taster, SpliceAI). The evolutionary conservation of novel missense variants was also investigated. Results: A total of 13 unrelated patients were identified: 2 (1 male; 1 female) with IMPG1 retinopathy and 11 (7 male; 4 female) with IMPG2 retinopathy. Both IMPG1 retinopathy patients were monoallelic: one patient had adult vitelliform macular dystrophy (AVMD) with drusenoid changes while the other had pattern dystrophy (PD), and they presented to clinic at age 81 and 72 years, respectively. There were 5 monoallelic IMPG2 retinopathy patients with a maculopathy phenotype, of whom 1 had PD and 4 had AVMD. The mean age of symptom onset of this group was 54.2 ± 11.8 years, mean age at presentation was 54.8 ± 11.5 years, and mean BCVAs were 0.15 ± 0.12 logMAR OD and −0.01 ± 0.12 logMAR OS. Six biallelic IMPG2 patients had RP with maculopathy, where the mean age of onset symptom onset was 18.4 years, mean age at examination was 68.7 years, and mean BCVAs were 1.90 logMAR OD and 1.82 logMAR OS. Variants in IMPG1 included one missense and one exon deletion. A total of 11 different IMPG2 variants were identified (4 missense, 7 truncating). A splicing defect was predicted for the c.871C>A p.(Arg291Ser) missense IMPG2 variant. One IMPG1 and five IMPG2 variants were novel. Conclusions: This study describes the phenotypic spectrum of IMPG1/IMPG2 retinopathy and six novel variants are reported. The phenotypes of PD and AVMD in monoallelic IMPG2 patients may result from haploinsufficiency, supported by the presence of truncating variants in both monoallelic and biallelic cases. The identification of novel variants expands the known genetic landscape of IMPG1 and IMPG2 retinopathies. These findings contribute to diagnostic accuracy, informed patient counselling regarding inheritance pattern, and may help guide recruitment for future therapeutic interventions. Full article

Plasma membrane Ca²⁺-ATPases (PMCA) are activated by calmodulin (CaM) via a C-terminal calmodulin-binding domain, CaMBD. Although specific mutations in this domain have been linked to disease, the broader impact of alternative substitutions across the interface remains unexplored. We applied an integrative in silico workflow to test six substitutions within CaMBD positions 1–18, L5R, N6I, I8T, V14E/D, and F18S, across PMCA isoforms 1–4. CaMBD sequences were aligned across isoforms, and candidates for substitutions were selected by conservation and nucleotide feasibility, prioritizing conserved or co-evolutionarily relevant sites, with substitutions possible by single-nucleotide change. PolyPhen-2 screened the impact of the substitutions on the protein functionality, the DisGeNET database was used to contextualize ATP2B genes with clinical phenotypes, and structural models plus binding free energy changes were estimated with AlphaFold3, FoldX, and MutaBind2. Effects were isoform and subregion dependent, with the strongest weakening toward the CaMBD C-terminus. V14E/D and F18S showed the largest and consistent predicted destabilization, consistent with disruption of conserved hydrophobic anchors. I8T and L5R had mixed outcomes depending on isoform, while N6I presented various scenarios with no clear effect. PolyPhen-2 classified most tested substitutions as damaging. Gene-disease evidence linked ATP2B to neurological, endocrine, and oncologic phenotypes, consistent with roles in Ca²⁺ homeostasis. Overall, CaMBD appears highly sensitive to perturbation, with distal positions 14–18 particularly vulnerable to substitutions that can destabilize CaM binding and potentially impair PMCA-mediated Ca²⁺ clearance in susceptible tissues. Full article

Facultative paedomorphosis, the retention of larval traits in sexually mature individuals, plays a crucial role in species ecology and evolution and is influenced by complex interactions between environmental factors. Here, we compile all known cases of paedomorphosis in all newt species in Greece and report 20 new localities, mainly in Northern Pindos National Park. Our results indicate that paedomorphosis tends to occur more frequently in stable aquatic environments in combination with unfavourable external conditions (lack of precipitation and higher temperatures). Furthermore, species-specific patterns related to the occurrence of paedomorphosis were also unveiled: Mesotriton alpestris prefers high-elevation and permanent ponds; Lissotriton graecus occurs predominantly in artificial, lowland ponds; and Triturus macedonicus is associated with a stable hydroperiod and fish absence. Overall, conservation strategies should explicitly account for paedomorphic populations, emphasizing the value of artificial ponds, which are able to support this life-history strategy. Lastly, the Northern Pindos Mountain Range emerges as a major European intra-specific diversity hotspot. Full article

Background: Breast and ovarian cancers (BC and OC) are prevalent malignancies in women globally, with germline variants in the BRCA2 gene significantly increasing the risk of developing these cancers. Despite extensive studies, the frequency and impact of BRCA2 variants in women from Jalisco, Mexico, remain underexplored. Objective: The aim of this study was to identify and characterize BRCA2 gene variants in Mexican women diagnosed with BC and OC and to assess their functional and structural consequences using computational analyses. Methodology: Genomic DNA from 140 Mexican women with BC and/or OC, selected based on clinical criteria suggestive of BRCA2 variants, was sequenced using NGS targeting BRCA2 coding regions. Functional effects were predicted with Ensembl VEP, SIFT, and PolyPhen-2. Structural impacts of missense variants were assessed using HOPE and AlphaFold models. Results: BRCA2 variants were identified in 12.86% of patients, with higher frequency in OC (21.05%) than BC (12%). Several mapped to key functional domains, including BRC repeats and the DNA-binding domain. Many were predicted as deleterious or probably damaging, though clinical classifications were often conflicting. Structural analysis indicated potential disruptions in protein stability or interactions for most missense variants. Clinically, BRCA2-positive BC patients were younger at diagnosis and showed a trend toward lower complete response. Conclusion: BRCA2 variants were found in 12.86% of patients, including six VUSs not reported in other populations. Several affected key functional domains with predicted deleterious effects. Findings support the need for genetic panels tailored to the Mexican population. Full article

Background: Wilson’s disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene, leading to copper accumulation in the liver and brain. Given the clinical heterogeneity of the disease, this study aimed to characterize the mutational spectrum of ATP7B and explore genotype–phenotype correlations in Turkish patients. Methods: Whole-exome sequencing (WES) was performed in 17 Turkish patients clinically diagnosed with WD. Variants were annotated and evaluated using five in silico prediction tools (REVEL, CADD, PolyPhen, SIFT, MutationTaster). Copy number variation (CNV) analysis was conducted using the CLC Genomics Server (Version 22.0.2). Results: A total of 14 distinct ATP7B variants were identified, comprising 12 missense, 1 nonsense, and 1 frameshift mutation. Variant distribution showed some phenotype-specific patterns: four variants were found more frequently in hepatic cases and three in neurological cases, although no statistically significant or consistent correlation between genotype and clinical presentation could be established. The most frequent mutation was p.His1069Gln, present in both phenotypes. All missense variants were predicted to be pathogenic by at least three computational tools, with high concordance among platforms. No pathogenic CNVs were detected. Conclusions: This study expands the mutational landscape of ATP7B in Turkish patients with WD and supports the utility of WES combined with in silico tools for accurate variant classification. The results emphasize the genetic heterogeneity of WD and suggest possible associations between certain mutations and clinical phenotypes. Full article

Background: Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower-limb spasticity and weakness. SPAST mutations are the most common cause of autosomal dominant HSP (SPG4). However, many pathogenic SPAST variants are unique and genetic data from underrepresented communities remain limited. Methods: Whole-exome sequencing (WES) was performed on the index patient with HSP. Variant annotation tools included Ensembl VEP, LOFTEE, CADD, SIFT, PolyPhen-2, MutationTaster, and SpliceAI. Variant interpretation followed ACMG/AMP guidelines. Clinical evaluation and family history supported phenotypic correlation and segregation. Results: A novel heterozygous frameshift variant in SPAST (c.339delG; p.Glu114Serfs*47) was identified. The variant was predicted to cause nonsense-mediated decay, resulting in loss of the microtubule-interacting and AAA ATPase domains of spastin. It was absent from population databases (gnomAD, TOPMed, 1000 Genomes) and public variant repositories (ClinVar, HGMD). The variant segregated with disease in two affected siblings and could be classified as likely pathogenic. Conclusions: This novel SPAST frameshift variant expands the mutational spectrum of SPG4-HSP and highlights the importance of including isolated or minority communities in genomic research to improve variant interpretation. Full article

Background/Objectives: CLIFAHDD syndrome (OMIM # 616266) is a rare neurodevelopmental disorder caused by mutations in the NALCN gene. It is characterized by hypotonia, developmental delay, and congenital contractures of the limbs and face. We report a 33-year-old Italian woman with a mild form of CLIFAHDD who exhibited early-onset language difficulties and mild intellectual disability and later developed gait and balance impairments in adulthood. Methods and Results: Whole Exome Sequencing (WES) identified a novel missense variant c.1514A>T; p.(Lys505Met) in the NALCN gene. The allele frequency of this variant is not detected (MAF = 0.0), the variant is classified as likely pathogenic according to ACMG criteria, and predicted to be probably damaging by PolyPhen-2. It affects a critical residue within the second pore-forming domain of the NALCN channel, potentially altering lipid interactions and channel regulation. Sanger sequencing and segregation analysis confirmed the variant to be heterozygous and de novo. Conclusions: The patient’s milder symptoms and later onset, compared to severe pediatric cases, suggest that the clinical spectrum of CLIFAHDD syndrome may be broader than previously recognized. These findings underscore the potential influence of mutation location on disease presentation and severity. Full article

Background/Objectives: The bird cherry-oat aphid, Rhopalosiphum padi, is a major global pest of cereal crops and exhibits wing polyphenism, producing both winged (dispersive) and wingless (reproductive) morphs. Methods: To identify potential RNAi targets that could specifically disrupt the migratory winged morph, we conducted a comparative transcriptomic analysis of adult aphids. Differentially expressed genes (DEGs) were identified, annotated for their functions, and analyzed for their involvement in metabolic pathways. Results: Significant differences were observed in 121 genes between morphs: 13 were upregulated in the winged morph, while 108 were downregulated. Most DEGs were enriched in lipid metabolism and circadian rhythm pathways, suggesting that wing polymorphism may be adaptively linked to energy resource allocation strategies. Conclusions: This study firstly reveals the adult-stage-specific regulatory roles of lipid metabolism and circadian rhythm pathways in wing polyphenism, identifying six candidate genes (BCORL1, AMP-L, Pfl, Lip3L, HLFL(X7), and HLFL(X4)) for RNAi-based biocontrol strategies targeting migratory morphs. Full article

Scrapie (classical and atypical) susceptibility in sheep is strongly influenced by PRNP gene polymorphisms. In Portugal, limited data exist for native breeds such as Serra da Estrela, despite their relevance to animal conservation and food production. The full coding region of PRNP gene of 92 Serra da Estrela sheep was sequenced and SNP frequencies were analysed. The predicted functional impact of nonsynonymous SNPs was assessed using PolyPhen-2 and AMYCO. A total of 27 SNPs were identified, including 20 nonsynonymous variants. Thirteen major haplotypes were observed. The ARR allele, which provides resistance to classical scrapie, was present in 58.7% of the population, with 18.5% of animals being homozygous. Several previously unreported SNPs were identified, and their impact on prion protein aggregation propensity and structure was explored. The high frequency of the ARR allele without full ARR fixation suggests that no selective breeding for scrapie resistance has been applied. These results support the adoption of gradual selection strategies that preserve genetic variability and promote farmer compliance, while increasing classical and atypical scrapie resistance. Full article

Background: RNF114 gene encodes an E3 ubiquitin ligase involved in immune signaling and regulation of inflammation. Genetic variants, particularly nonsynonymous single-nucleotide polymorphisms (nsSNPs), may interfere with protein function and cause immune diseases such as psoriasis. Although significant, the structural and functional impact of RNF114 nsSNPs is not well understood. Methods: We used comprehensive bioinformatics analyses to predict the functional impact of RNF114 nsSNPs. Deleterious variants were predicted by SIFT, PolyPhen-2, PROVEAN, META-SNP, ESNP&GO, PANTHER, and Alpha-Missense. Protein stability was examined by I-Mutant2.0, and MUpro further contextualized variant effects. Structural modeling was performed by AlphaFold and visualized using UCSF ChimeraX 1.10.1. Additionally, we studied the Conservation using ConSurf and protein-protein interaction by STRING tools. Results: Among 252 available nsSNPs, three mutations—C49R (rs1600868749), R68C (rs745318334), and R68H (rs758000156)—were predicted to have a deleterious and destabilizing effects on the protein structure by all the tools. All three variants were located in extremely conserved residues and were predicted to significantly destabilize the protein structure. Structural modeling demonstrated disruptions in the RNF114 domain structure. STRING analysis revealed interactions of RNF114 with key immune regulators, and pathway enrichment pointed to roles in NF-κB signaling, ubiquitin-mediated proteolysis, and autoimmune disease pathways. Conclusions: In the current study, we predicted three novel, potentially pathogenic RNF114 variants with protein-destabilizing effect that could lead to immune dysregulation. Full article

Hearing loss is often caused by genetic and environmental factors, with inherited mutations responsible for 50–60% of cases. The GJB2 gene, encoding connexin 26, is a major contributor to nonsyndromic sensorineural hearing loss (NSHL) due to its role in cellular communication critical for auditory function. In Taiwan, common deafness-associated genes include GJB2, SLC26A4, OTOF, MYO15A, and MTRNR1, which were similar to those found in other populations. The most common pathogenic genes is GJB2 mutations and the hearing level in children with GJB2 p.V37I/p.V37I or p.V37I/c.235delC was estimated to deteriorate at approximately 1 decibel hearing level (dB HL)/year. We found another common mutation in Taiwan Biobank, GJB2 p.I203T, which were identified in our data and individuals carrying this mutation experienced more severe hearing loss, suggesting a synergistic effect of these mutations on auditory impairment. We suggest GJB2 whole genetic screening is recommended for clinical management and prevention strategies in Taiwan. This study used data from the Taiwan Biobank to analyze allele frequencies of GJB2 gene variants. Predictive software (PolyPhen-2 version 2.2, SIFT for missense variants 6.2.1, MutationTaster Ensembl 112 and Alphamissense CC BY-NC-SA 4.0) assessed the pathogenicity of specific mutations. Additionally, 82 unrelated NSHL patients were screened for mutations in these genes using PCR and DNA sequencing. The study explored the correlation between genetic mutations and the severity of hearing loss in patients. Several common GJB2 mutation sites were identified from the Taiwan Biobank, including GJB2 p.V37I (7.7%), GJB2 p.I203T (6%), GJB2 p.V27I (31%), and GJB2 p.E114G (22%). Bioinformatics analysis classified GJB2 p.I203T as pathogenic, while GJB2 p.V27I and GJB2 p.E114G were considered polymorphisms. Patients with GJB2 p.I203T mutation experienced more severe hearing loss, emphasizing the potential interaction between the gene in auditory impairment. The mutation patterns of GJB2 in the Taiwanese population are similar to other East Asian regions. Although GJB2 mutations represent the predominant genetic cause of hereditary hearing loss, the corresponding mutant proteins exhibit detectable aggregation, particularly at cell–cell junctions, suggesting at least partial trafficking to the plasma membrane. Genetic screening for these mutations—especially GJB2 p.I203T (6%), GJB2 p.V27I (31%), and GJB2 p.E114G (22%)—is essential for the effective diagnosis and management of non-syndromic hearing loss (NSHL) in Taiwan. We found GJB2 p.I203T which were identified in our data and individuals carrying this mutation experienced more severe hearing loss, suggesting a synergistic effect of these mutations on auditory impairment. We suggest whole GJB2 gene sequencing in genetic screening is recommended for clinical management and prevention strategies in Taiwan. These findings have significant clinical and public health implications for the development of preventive and therapeutic strategies. Full article

The migratory locust (Locusta migratoria), is a destructive pest in agriculture and ecological conservation, characterized by its unique phase polyphenism (phase change). Parthenogenesis, defined as oviparous reproduction without fertilization, has been studied less extensively than fertilized reproduction, with particularly scarce research on parthenogenesis in migratory locust. This study investigates the relationship between parthenogenesis and the phase change in migratory locusts. Through comparative studies between two phases, we found that solitary locusts exhibit a higher parthenogenesis capacity compared to gregarious locusts, as evidenced by greater total oviposition quantity and higher hatching rates. However, parthenogenesis resulted in significantly lower hatching rates compared to sexually fertilized females, with distinct differences in oviposition dynamics and hatching patterns. Furthermore, we observed that gregarious locusts, when isolated after eclosion, exhibited increased parthenogenetic capacity, depending on their juvenile density. Together, this study provides insights into the understanding of insect parthenogenesis and lays basis for the potential underlying mechanism. Full article

Osteoporosis is a common disease characterized by a reduction in bone mineral density (BMD), leading to an increased risk of pathological fractures and even mortality. Although menopause is a major risk factor, osteoporosis can also occur in premenopausal women. The aim of this study was to identify genetic variants associated with the development of osteoporosis in Korean premenopausal women. Subjects were recruited from the Anseong and Ansan cohorts of the Korean Genome and Epidemiology Study (KoGES). Clinical and epidemiological characteristics were assessed, and participants were classified based on BMD values measured at the distal radius and mid-shaft tibia. Individuals with confounding risk factors such as low body weight, smoking, high alcohol consumption, steroid/hormone therapy, or relevant medical history were excluded. A total of 247 healthy controls and 57 osteoporosis patients were included. Genotyping was performed using the Illumina Infinium HumanExome BeadChip and the Affymetrix Axiom Exome Array. Data were analyzed using the SNP and Variation Suite and PLINK, with quality control thresholds set at MAF ≥ 0.05 and HWE p ≥ 0.01. Functional annotation and protein structure predictions were performed using PolyPhen-2, SIFT, and PROVEAN. Genome-wide association analyses identified 113 single-nucleotide polymorphisms (SNPs) in 69 genes significantly associated with osteoporosis (p < 0.05) in both platforms, with 18 SNPs showing high cross-platform consistency (p < 0.01). Several of these genes were implicated in bone metabolism (e.g., ESRRG, PECAM1, COL6A5), vitamin D metabolism (e.g., NADSYN1, EFTUD1), skeletal muscle function (e.g., PACSIN2, ESRRG), and reproductive processes (e.g., CPEB1, EFCAB6, ASXL3). Notably, the CPEB1 rs783540 SNP exhibited the strongest association (p < 0.001) in both analyses. Our findings suggest that genetic polymorphisms in pathways related to bone metabolism, vitamin D signaling, muscle–bone interaction, and reproductive hormone regulation may contribute to the development of osteoporosis in Korean premenopausal women. These results provide a genetic basis for early identification of at-risk individuals and warrant further functional studies to elucidate the underlying mechanisms. Full article

Background: Amyotrophic lateral sclerosis is a systemic, complex, multifactorial, and fatal neurodegenerative disease with various factors involved in its etiology. This study aimed to understand the effects of SNPs in the MTHFR, MTR, SLC19A1, and VAPB genes on protein functionality and structure and their influence on ALS susceptibility. Methods: The dbSNP and ClinVar databases were used for SNP data annotation, while UniProt and PDB provided protein sequences. We performed functional and structural predictions of SNPs using PolyPhen-2 and SNAP2. We modeled mutant proteins using AlphaFold 2 and visualized them in PyMOL to compare native and mutant forms. Results: Our results identified SNP rs74315431 as pathogenic, inducing structural and functional changes and exhibiting visible alterations in the three-dimensional structure. Although predicted as non-pathogenic, SNPs rs1801131, rs1805087, and rs1051266 caused protein structural alterations, a finding confirmed by three-dimensional visualization. SNP rs1801133 diverged from the others, being predicted as pathogenic but without causing changes in protein structure or function. Conclusions: Our study found a strong correlation between SNAP2-predicted alterations and those predicted by AlphaFold 2, whereas PolyPhen-2 results did not directly correlate with three-dimensional structure changes. Full article