Search Results (1,110)

KRTAP24-1 belongs to the high-sulphur KAP family and has been associated with cashmere fibre diameter in goats, but its role in ovine wool traits remains unclear. This study assessed KRTAP24-1 tissue expression by RT-qPCR and investigated genetic variation and associations with wool traits in 277 Tibetan sheep. Polymorphisms in the coding region were identified by PCR amplification and Sanger sequencing, and genotyping was performed using PARMS. A linear mixed model (LMM) incorporating a genomic relationship matrix (GRM) was used to evaluate associations between SNPs, haplotypes, and 12 wool traits. Bioinformatic analyses were restricted to the five haplotypes observed in the study population and were used as preliminary in silico assessments. Three missense SNPs were identified: c.191C>T (p.L64P), c.527G>A (p.G176D), and c.656C>T (p.A219V). The c.191C>T variant was associated with mean fibre length (MFL), single fibre tenacity (SFT), and scoured yield (SY), whereas c.656C>T was associated with lock length (LL) and clean fleece yield (CFY). Several haplotype combinations were also associated with LL, elongation at break (EB), and CFY. KRTAP24-1 showed high expression in skin. The observed haplotypes showed only minor differences in predicted mRNA secondary structure and mainly local changes in predicted protein features. These findings suggest that KRTAP24-1 may provide a preliminary basis for marker-assisted selection in Tibetan sheep breeding, but its functional role requires further validation in independent populations and experimental systems. Full article

The BRCA1 protein serves an essential function in maintaining genomic integrity, to the extent that up to 80% of women carrying a pathogenic BRCA1 variant develop breast cancer (BC). Most of these carriers would benefit from prophylactic care, but genetic screens that uncover variants of uncertain significance (VUSs) do not provide insight on disease risk or clinical decision-making. In accordance with guidelines established by The American College of Molecular Genetics (ACMG) and Association for Molecular Pathology (AMP), this study produced computational and functional evidence to inform the reclassification of BRCA1 VUSs as pathogenic or benign, with a specific focus on the abundant subset of missense variants within the RING domain. A six-feature linear support vector machine (LSVM) specifically trained on BRCA1 RING variants performed well (84% accurate in predicting in vitro binding loss) and provided supporting classification evidence for 322 VUS. A mammalian cell co-immunoprecipitation (co-IP) assay that quantified the binding between variant BRCA RING constructs and endogenous BARD1 provided corroborating strong evidence for nine VUSs and correlated with a homology-directed repair (HDR) assay by Starita et al. (p = 0.04). The combined evidence warrants the reclassification of three VUSs as likely benign (N16S, A17D, and E100D) and one as likely pathogenic (H41P), and underscores the promise of domain-specific approaches for missense VUS reclassification. Full article

Obesity and metabolic dysregulation are closely associated with chronic low-grade inflammation, in which interleukin-6 (IL-6) plays a key regulatory role. Genetic variation in the IL-6 gene may influence inflammatory responses and metabolic homeostasis. To identify single-nucleotide variants (SNVs) in the IL-6 gene in a cohort of Colombian high-performance athletes and to evaluate their potential functional and structural consequences using bioinformatic prediction and protein-modeling approaches. A descriptive observational study was conducted in a cohort of 23 high-performance Colombian athletes from Valle del Cauca representing cycling, karate, and weightlifting disciplines. Genomic Deoxyribonucleic Acid (DNA) extracted from peripheral blood samples was analyzed using Next-Generation Sequencing (NGS). Identified variants were evaluated using several in silico prediction tools, including Basic Local Alignment Search Tool (BLAST version 2.16.0), Expert Protein Analysis System (ExPASy version 4.0), Open Reading Frame Finder (ORFfinder version 0.4.3), and population databases such as Genome Aggregation Database (gnomAD version 4.0). Structural modeling was used to explore the potential impact of amino-acid substitutions on IL-6 protein stability. Eight single-nucleotide variants were identified in the IL-6 gene. Among them, the rs1524107 variant generated a missense substitution predicted to modify the amino-acid sequence of the IL-6 protein. Structural modeling suggested a potential alteration in protein stability associated with this variant. The rs1524107 variant may influence IL-6 protein structure according to computational predictions. These findings provide preliminary hypothesis-generating evidence regarding the potential role of IL-6 genetic variation in inflammatory regulation; however, functional validation and larger cohort studies are required to determine their biological significance. Full article

Background/Objectives: Genome-Wide Association Studies (GWASs) have revealed numerous Single Nucleotide Polymorphisms (SNPs) linked to diverse diseases and traits, highlighting extensive pleiotropy. This study aimed to identify functionally relevant pleiotropic genes through large-scale analysis of the GWAS catalog and variant annotation. Methods: An initial set of 494 putative pleiotropic genes across 223 phenotypes was refined using stringent criteria, yielding 343 SNP–trait associations corresponding to 53 SNPs mapped to 16 genes. Results: Five top-ranked genes were prioritized using a composite score, and their variants were fully annotated for genetic and clinical features. Approximately 70% of the SNPs were intronic, with five located in UTRs, and 11 in coding regions. ABO emerged as the highest-scoring pleiotropic gene, with six SNPs in strong linkage disequilibrium, implicating rs8176719 (c.261delG in exon 6) as the likely causal variant. ALDH2 showed 20 strong associations across two SNPs, with rs671 (E504K) identified as a key missense variant linked to multiple diseases. GCKR exhibited 29 associations across three SNPs, with rs1260326 (P446L) reducing glucokinase inhibition and enhancing hepatic glycolysis and triglyceride production. In HLA-DQA1, three of four SNPs located in UTRs suggested regulatory roles in gene expression. TERT displayed 59 GWAS signals, primarily cancer-related across seven organs, involving eight SNPs. Among these, rs10069690 in intron 4 has been associated with altered gene expression, while the functional impact of other variants remains to be clarified. Conclusions: This work highlights key pleiotropic genes and variants, offering insights into the genetic architecture and mechanisms underlying complex human diseases. Full article

Background: PURA-related neurodevelopmental disorder (PURA-NDD; OMIM #616158) is a rare autosomal dominant condition caused by pathogenic variants in the PURA gene encoding Purα, a multifunctional protein involved in DNA replication, transcriptional regulation, and RNA transport. Since its initial description in 2014, PURA-NDD has been increasingly recognized as a distinct clinical entity with early onset and a broad phenotypic spectrum. The clinical presentation is characterized primarily by neonatal hypotonia, global developmental delay, intellectual disability, feeding difficulties, and epilepsy, along with additional features such as respiratory insufficiency, movement disorders, hypersomnolence, and variable dysmorphic traits. Despite a relatively recognizable core phenotype, marked inter-individual variability often limits the ability to establish a definitive clinical diagnosis based on phenotype alone. This underscores the essential role of molecular genetic testing in the differential diagnosis of rare neurodevelopmental disorders. Patients and methods: We report a cohort of eight individuals (four males and four females) aged 17 months to 15.5 years with PURA-related neurodevelopmental disorder (PURA-NDD), evaluated using a genotype-first diagnostic strategy supported by comprehensive genomic testing, including next-generation sequencing (NGS) panels and whole-genome sequencing (WGS). Patients were referred for the evaluation of nonspecific neurodevelopmental features, including neonatal hypotonia, respiratory distress, and epilepsy, in the absence of a definitive clinical diagnosis. Results: Molecular analysis identified eight heterozygous variants in PURA, of which four (50%) were novel: c.311T>G p.(Met104Arg), c.406_407del p.(Gln136Glyfs64), c.515A>C p.(Gln172Pro), and c.885delinsGC p.(His296Profs21). The remaining variants included previously reported missense and frameshift changes associated with PURA-NDD, as well as one variant previously reported in ClinVar. Conclusions: Our findings not only confirm the core clinical features of PURA-related neurodevelopmental disorder but also contribute to a more comprehensive delineation of its phenotypic spectrum. The detailed characterization of our cohort broadens the range of recognized clinical manifestations and further highlights the marked phenotypic heterogeneity of PURA-NDD. In addition, the identification of both novel and previously reported pathogenic variants expands the mutational spectrum of PURA and underscores the importance of integrating clinical, molecular, and bioinformatic data for accurate variant interpretation. Although genotype–phenotype correlations remain incompletely understood, emerging evidence suggests potential associations between variant type or location and clinical severity, warranting further investigation in larger cohorts. The recognition of characteristic neonatal features may facilitate earlier diagnosis and implementation of supportive multidisciplinary management. Overall, this study illustrates how genomic technologies not only improve diagnostic yield in rare disorders but also refine disease definition, enhance the understanding of underlying pathogenic mechanisms, and support the development of more precise genotype–phenotype correlations. Further studies involving larger cohorts and long-term follow-up are needed to better define the full clinical and molecular spectrum of PURA-NDD. Full article

Background: Mutations in the FBXO7 gene (PARK15) cause an autosomal recessive, early-onset neurodegenerative disorder typically presenting as Parkinsonian-Pyramidal Syndrome (PPS). Despite its recognition, the high phenotypic variability often delays diagnosis. Here, we report a novel Italian family and synthesize data from all published cases to date, offering an updated clinical and molecular overview of the disease. Methods: We performed clinical and molecular characterization of a newly identified family. Furthermore, we conducted a systematic literature review (from 2008 to 2026) to aggregate clinical, genetic, and geographic data of all reported PARK15 cases. Results: Two siblings presented with a complex phenotype including early-onset parkinsonism, cognitive decline, psychiatric symptoms, and aphasia-type speech disorders. Genetic analyses identified two novel likely pathogenic variants: a missense substitution in the UBL domain (p.Ile74Met) and a frameshift indel (p.Val233GlufsTer8). The literature review (incorporating clinical data from Europe, Asia, and South America) confirms a high prevalence of postural instability (87.5%), bradykinesia (83.3%), and pyramidal signs (~60%). We observed a distinct distribution of variants: missense mutations cluster in the N-terminal UBL and F-box domains, while truncating variants are more common in the C-terminal region. Discussion: Our findings expand the FBXO7 mutational landscape and underscore the “atypical” clinical markers, such as pyramidal signs and cognitive decline, that distinguish PARK15 from other recessive forms of parkinsonism like PARK2 and PARK6. The dual role of FBXO7 in mitochondrial quality control and proteasomal assembly suggests a broad disruption of cellular homeostasis. These observations refine genotype–phenotype correlations and may guide variant interpretation in routine diagnostic settings. Full article

Background and Objectives: A subset of cancer patients treated with immune checkpoint inhibitors may experience rapid tumor progression rather than therapeutic benefit, a phenomenon described as hyperprogressive disease (HPD), which is linked to poor prognosis and shortened survival. Reliable biomarkers capable of predicting HPD remain lacking. To better understand the molecular background of HPD, we analyzed promoter region methylation and somatic mutation profiles in cancer-related genes in patients with malignant melanoma (MM) and renal cell carcinoma (RCC) undergoing anti-PD-1/PD-L1 treatment. Methods: Patients diagnosed with MM or RCC and treated with anti-PD-1/PD-L1 agents between 2011 and 2020 were included, and FFPE tumor samples along with paired normal tissues were analyzed. A diagnosis of HPD was assigned to patients with RECIST 1.1-defined progressive disease who demonstrated a ≥2-fold acceleration in tumor growth kinetics after initiation of immune checkpoint inhibitor therapy. Methylation-specific real-time PCR was performed on 54 samples (15 MM tumors, 22 RCC tumors, 17 RCC-matched adjacent normal samples) to assess promoter methylation of PIK3CA, BAP1, PTEN, and TP53. Next-generation sequencing (NGS) with an 86-gene pan-cancer panel was conducted on 9 HPD samples. Results: Promoter hypermethylation involving PIK3CA, BAP1, PTEN, and TP53 was more pronounced in HPD-associated tumor samples (n = 16) than in tumors without HPD (n = 21). Within the MM cohort, PTEN and TP53 methylation levels demonstrated statistically significant differences between the two groups (p = 0.005 and p = 0.028, respectively), while no comparable associations were observed in RCC patients. NGS analysis detected missense mutations classified as pathogenic or likely pathogenic in 5 of 9 HPD patients (55.6%), involving KIT, PTEN, and VHL. Conclusions: Promoter region hypermethylation in cancer-related genes may contribute to the aggressive tumor behavior observed in HPD. The somatic variants identified in HPD patients are consistent with known oncogenic pathways. These findings support further investigation of epigenetic and genomic biomarkers for HPD risk stratification in larger, prospective cohorts. Full article

Background/Objectives: In recent years, efforts to understand obesity’s pathophysiology have focused on satiety signals in the hypothalamus and hormonal signalling in orexigenic and anorexigenic neurons. These signals, linked to hunger, satiety, and energy expenditure, are influenced by peptides that activate or suppress specific pathways. However, different phenotypes related to body composition result from mutations (allelic variants) in genes that encode these proteins, particularly peptide receptors. Specifically, the hormone receptor ghrelin (GHSR), located on the surface of orexigenic neurons, has been linked to the regulation of hunger. Additionally, the production and secretion of ghrelin, a peptide hormone produced by the stomach, may exhibit varying sensitivity in its receptor based on an individual’s nutritional status. Moreover, allelic variants of the GHSR gene may potentially lead to significant alterations in signalling provided by the GHSR receptor, resulting in modified hormone-binding phenotypes. In this context, the search for allelic variants that can account for diverse phenotypes, whether thinness or overweight/obesity, can aid in comprehending the pathway and defining new strategies for early laboratory diagnosis or target peptides for treatment. Methods: Initial mining produced 373 non-random SNPs located in missense regions. A total of 373 missense variants were initially identified in the GHSR gene. After applying a global minor allele frequency (MAF) filter of <1%, 20 rare missense variants remained. Results: These variants were subsequently analyzed using nine in silico pathogenicity prediction tools, resulting in the prioritization of eight variants predicted as deleterious by at least four algorithms. These variants were further analysed using the HOPE project web server and the SwissModel database. Conclusions: Through these analyses and future investigations into these mutations, we may gain a more comprehensive understanding of the implications of these mutations and their potential correlation with the pathophysiology of obesity. Full article

Background/Objectives: Fibronectin glomerulopathy (FNG) is a rare autosomal dominant inherited kidney disease. Approximately 40% of genetically confirmed FNG cases are associated with likely pathogenic variants in FN1. Patients with FNG have similar clinical features as those with chronic nephritis. Due to nonspecific clinical manifestations mimicking common childhood glomerular diseases, FNG poses significant diagnostic challenges in children, frequently resulting in delayed diagnosis. Case Description: A 9-year-old Chinese girl presented with manifestations suggestive of acute poststreptococcal glomerulonephritis (APSGN), including edema, hypertension, hypocomplementemia, nephrotic-range proteinuria (3.34 g/24 h), and microscopic hematuria (45–55 cells/HP). Despite resolution of edema and normalized complement C3 after initial therapy, proteinuria and hematuria persisted. Renal biopsy revealed prominent mesangial deposits extending to glomerular capillary walls, with strong fibronectin (FN) immunoreactivity and fibrillary electrondense deposits on electron microscopy. Genetic testing identified a heterozygous FN1 missense variant c.3051G>C (p.Trp1017Cys) in the proband and her asymptomatic father, classified as likely pathogenic per ACMG guidelines (supporting evidence: PS1, PM2, PP3, PP4). mRNA and cDNA sequencing confirmed the transcription of the mutant allele in the family members. Notably, these transcriptional analyses cannot provide direct evidence for the functional pathogenicity of the variant. The patient received combined angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy, and renal function remained stable during 3 years of follow-up. Conclusions: The FN1 c.3051G>C represents a novel nucleotide variant, while the corresponding amino acid alteration p.Trp1017Cys has been reported in the previous literature. This case expands the variant spectrum of FN1 and emphasizes the critical value of renal biopsy and genetic testing for diagnosing FNG in pediatric patients with persistent renal manifestations after suspected APSGN. Family screening is essential for identifying asymptomatic carriers. Our findings also highlight the phenotypic heterogeneity of FNG. Full article

Background/Objectives: L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder marked by developmental delay, intellectual disability, and progressive movement abnormalities. Variants in RYR1 can cause congenital myopathies, but data on the co-occurrence of variants in populations are limited. The aim of this study was to characterize the clinical and genetic basis of the neurometabolic and neuromuscular abnormalities and to investigate the potential interaction between the identified variants. Methods: Patients with complex, previously undiagnosed clinical presentations underwent neurological evaluation, including brain magnetic resonance imaging, electromyography, biochemical testing, and whole-exome sequencing (WES). Identified variants were analyzed in silico and confirmed by Sanger sequencing in the patient and her parents. Three cases were reviewed, and one of these patients exhibited developmental delay, hypotonia, intellectual disability, and progressive motor dysfunction. Biochemical tests revealed markedly elevated urinary 2-hydroxyglutaric acid levels, consistent with L2HGA. Results: WES identified a homozygous likely pathogenic variant in L2HGDH (c.589_590insGGC, p.Q197insG), confirming the molecular diagnosis of L2HGA. In addition, a heterozygous missense variant in RYR1 (c.7268T>A, p.M2423K), classified as a variant of uncertain significance, was detected and was inherited from her mildly affected father. The L2HGDH variant explains the neurometabolic phenotype of the patient, whereas the RYR1 variant remains of uncertain significance, and its clinical contribution cannot be clearly established. Conclusions: To our knowledge, this case illustrates the co-occurrence of a likely pathogenic L2HGDH variant and a heterozygous RYR1 variant of uncertain significance. The findings expand the mutational spectrum of L2HGA and underscore the value of comprehensive genomic testing in complex neurometabolic and neuromuscular disorders. Full article

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has fundamentally transformed the treatment landscape for relapsed and refractory B-cell malignancies, yet antigen escape remains a persistent therapeutic challenge that limits long-term remission durability. While antigen loss is typically considered a somatic event acquired during tumor evolution under therapeutic selective pressure, germline CD19 polymorphisms could theoretically influence CAR-binding kinetics, alter epitope presentation, and modulate therapeutic outcomes in ways that remain largely not characterized. Unfortunately, Middle Eastern populations are underrepresented in pharmacogenomic databases and CAR-T clinical trials, creating a knowledge gap that may perpetuate global health disparities in access to precision immunotherapy. We analyzed publicly available whole-exome sequencing data from 1196 individuals of Arab origin to comprehensively characterize CD19 variants with potential relevance to CAR T-cell immunotherapy. The L174V (rs2904880) variant stood out, and showed the Valine/Valine (V/V) genotype frequency was 65.3%, corresponding to a V174 allelic frequency of 76.6%, while the minor allele, L174, has a frequency of 23.4%. The missense mutation (c.520C > G) responsible for this variant results in a leucine-to-valine (L174V) substitution at position 174 of the CD19 protein, relative to the reference genome. The cohort genotypes (CC, CG, and GG) exhibited a significant deviation from Hardy–Weinberg equilibrium (p < 0.00001). While this deviation is consistent with the high consanguinity rates (25–60%) amongst Arab populations, it remains not fully explained, and may be attributed to population structure, relatedness, or technical factors. We further emphasize that our computational analysis cannot establish any direct clinical or functional impact due to this variant, and therefore we refrain from suggesting any specific actions at the current time. In light of these findings, we hypothesize that the distinctive genetic architecture of consanguineous populations should not be viewed as a confounding variable. Instead, it presents a unique opportunity to investigate the clinical relevance of germline variation in the context of precision oncology, particularly at therapy-relevant loci, pending functional validation. Full article

Objectives: The aim of this study was to report novel ABCA4 variants detected in a cohort of 259 patients with ABCA4 retinopathy with the intention of improving the diagnostic accuracy for ABCA4 retinopathy and expanding its genetic spectrum. Methods: We retrospectively reviewed 259 patients with ABCA4 retinopathy, comprising 190 patients from the Oxford Cohort and 69 patients from other centres with a clinical diagnosis of ABCA4 retinopathy who were referred for genetic testing. Patients with a phenotype consistent with ABCA4 retinopathy who had a novel ABCA4 variant were included. Phenotyping in the Oxford Cohort included clinical evaluation, retinal imaging, and electrodiagnostic testing. Genetic testing was performed using next-generation sequencing (NGS) and Sanger sequencing. In silico analysis was used to investigate the pathogenicity of novel variants. Results: Eleven novel variants were detected in 12/259 patients, with one variant detected in two unrelated patients. These variants included three missense, four truncating, three splice-site variants, and one exon deletion. The variants were distributed across eight exons and three introns of ABCA4. In silico analysis and phenotype correlation supported the potential pathogenicity of the novel variants. Phenotypes ranged from mild isolated flecks with preserved retinal architecture to extensive chorioretinal degeneration. Conclusions: Despite over 2200 ABCA4 variants being reported to date, a further 11 novel ABCA4 variants were identified in 259 patients using NGS panel-based sequencing and MLPA. The variants were located across the whole ABCA4 gene, emphasising the necessity to sequence the whole gene. Our reporting of these variants expands the known genetic spectrum of ABCA4 retinopathy, contributing to accurate diagnosis in this patient group and the identification of suitable patients for recruitment to potential therapeutic interventions. Full article

Background/Objectives: The genes encoding HSPA1A, HSPA1B, and HSPA1L, located in the MHC class III region at 6p21.3–22.1, a region implicated in susceptibility to schizophrenia, are critical regulators of neurodevelopmental processes and contribute to synaptic neuroprotection. This study investigated whether the HSPA1A, HSPA1B, and HSPA1L genes are associated with schizophrenia. Methods: We sequenced the coding regions of HSPA1A, HSPA1B, and HSPA1L from 100 patients with schizophrenia to identify genetic variants. Further, we conducted a genetic association analysis of three SNPs (rs9469057, rs142416335, and rs2075800) in the HSPA1L gene in 519 patients with schizophrenia and 1492 healthy controls from the Taiwan Biobank. We analyzed the function of the HSPA1L protein via immunoblotting. Results: We identified 17 coding variants, including 8 missense and 9 synonymous mutations, in 100 patients with schizophrenia. Three variants (HSPA1L^p.Ala8Pro, HSPA1L^p.Ala8Thr, and HSPA1L^p.Glu602Lys) in the HSPA1L gene did not exhibit any significant differences in allele or genotype frequencies between patients and control subjects. Notably, one ultra-rare missense mutation, HSPA1L^p.Val262Met, was not documented in the control sample in Taiwan BioBank. Immunoblotting revealed HSPA1L^p.Val262Met mutant with decreased protein expression in SH-SY5Y cells compared with the wild type. Conclusions: While common variants in the HSPA1A, HSPA1B, and HSPA1L genes do not seem to be significant genetic risk factors for schizophrenia in this cohort, the ultra-rare mutation, HSPA1L^p.Val262Met, significantly reduces protein expression. These preliminary findings suggest that a potential loss-of-function or reduced expression of the HSPA1L gene may be a predisposing factor contributing to schizophrenia vulnerability in certain individuals. However, the finding should be replicated in other independent samples. The in vitro and in vivo impacts of the associated mutation at the HSPA1L gene on the pathophysiology of schizophrenia are worthy of future investigation. Full article

RPE65, an isomerohydrolase expressed in retinal pigment epithelium (RPE), is critical for the visual cycle. More than 115 missense variants of the RPE65 gene have been associated with Leber’s congenital amaurosis (LCA), a severe childhood retinal dystrophy. Due to high genetic heterogeneity, the variant-specific pathogenic mechanisms remain largely uncharacterized. In this study we focus on an LCA patient carrying compound heterozygous RPE65 variants (c.200T > G, c.430T > C), aiming to dissect the mechanistic/functional basis of mutated protein-driven retinal degeneration and evaluate gene therapy-mediated restoration using patient-specific hiPSCs-RPE (iRPE). Transient overexpression of wild-type/mutant RPE65 in HEK293T cells showed both variants markedly destabilize the RPE65 protein through the autophagosome–lysosome degradation pathway and its isomerohydrolase activity required for the retinoid visual cycle. We further established a patient-specific iRPE platform suitable for enzymatic activity analysis. Characterization of patient-specific iRPE cells revealed those compound heterozygous variants did not compromise iRPE morphology, most gene expression, or core canonical physiological features of iRPE. However, they significantly downregulate endogenous RPE65 protein abundance and dampen enzymatic function. Subsequently, we delivered RPE65 via adeno-associated viral (AAV) vectors driven by either the ubiquitous CMV promoter or RPE-specific VMD2 promoter into patient iRPE to validate therapeutic potency, and verified that exogenous RPE65 supplementation effectively restores deficient isomerohydrolase activity in this disease model. Collectively, this work elucidates the variant-specific pathogenesis of RPE65-associated LCA and preliminarily assesses the efficacy of gene augmentation, providing preclinical experimental evidence to support the referral of this patient for clinical RPE65 gene replacement therapy. Full article

The Popeye domain-containing protein 1 (Popdc1), also known as Bves, plays a crucial role in maintaining skeletal muscle homeostasis, with its variants leading to limb–girdle muscular dystrophy type R25. Skeletal muscles of patients with the homozygous missense variant of Bves exhibit impaired membrane trafficking, while skeletal muscle fibers in bves^S191F homozygous mutant zebrafish are significantly reduced and disorganized. However, the mechanism by which the absence of bves induces skeletal muscle atrophy remains unclear. In this study, we discovered a novel mechanism whereby bves deficiency drives skeletal muscle atrophy by disrupting mitochondrial structure and function. Our findings indicate that bves knockout leads to a significant decrease in zebrafish’s ability to swim, atrophy of skeletal muscle tissue, loss of cell membrane localization signals, and abnormalities in mitochondrial structure and function. After an 8-week intervention of regular aerobic exercise, the symptoms of skeletal muscle atrophy in bves knockout zebrafish were significantly alleviated, and the expression levels of genes and proteins related to mitochondrial were effectively rescued. These findings establish a connection between bves deficiency-induced disruption of mitochondrial structure and function and the onset and progression of skeletal muscle tissue atrophy symptoms, thereby laying a molecular foundation for exercise rehabilitation strategies in atrophic myopathy. Full article