Association between fok1 polymorphism of vitamin D receptor gene with uterine leiomyoma in Turkish populations

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson’s disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a novel gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal lethality with neurological manifestations across 17 pedigrees with 24 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy, and may affect proteasomal abundance and assembly in patient-derived fibroblasts. Furthermore, Drosophila and mouse models of PSMF1 loss of function exhibit age-dependent motor impairment, as well as brain-wide mitochondrial membrane depolarization and dopaminergic neurodegeneration in aged flies, and diffuse gliosis in mice. Collectively, our findings unequivocally link defective PSMF1 to early-onset parkinsonism and neurodegeneration, and suggest proteasomal and mitochondrial dysfunction as mechanistic contributors.

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson’s disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here we identify PSMF1 as a gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal lethality with neurological manifestations across 18 pedigrees with 25 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/hPI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants may affect proteasomal abundance and assembly, and are associated with alterations of mitochondrial membrane potential, respiration, dynamics and mitophagy in patient-derived fibroblasts. Furthermore, Drosophila and mouse models of PI31 loss of function exhibit age-dependent motor impairment, as well as brain-wide mitochondrial membrane depolarization and dopaminergic neurodegeneration in aged flies, and diffuse gliosis in mice. Collectively, our findings unequivocally link defective PSMF1/hPI31 to early-onset parkinsonism and neurodegeneration, and suggest proteasomal and mitochondrial dysfunction as pathogenic contributors.

Short tandem repeat (STR) expansions are a major cause of neurodegenerative disorders; however, their genetic and clinical heterogeneity complicates diagnosis. STR detection remains limited in routine short-read next-generation sequencing (NGS) workflows. We evaluated the diagnostic yield and clinical utility of computational STR genotyping in a large Turkish neurodegenerative disease cohort. ExpansionHunter was applied to NGS data from 3150 patients and 146 controls, targeting 15 disease-associated STR loci. To improve genotyping of poorly captured exonic regions in exome data, the default locus coverage threshold was reduced from 10× to 3×. Candidate expansions were visually inspected using REViewer and validated by conventional molecular methods. Computational analysis detected 28 pathogenic and 160 intermediate expansions. Of these, 23 were confirmed as pathogenic, and eight initially classified as intermediate were reclassified as pathogenic after conventional validation, resulting in 31 pathogenic cases across 28 families: HTT (n = 8), ATXN2 (n = 5), ATXN1 (n = 4), DMPK (n = 3), PABPN1 (n = 3), TBP (n = 2), and single cases in AR, ATN1, and CACNA1A. Lowering the coverage threshold markedly increased genotyping rates at low-coverage loci in exome data, particularly in ATXN2. Genetic findings were largely consistent with clinical pre-diagnosis and the additional diagnostic yield was 0.95%. These findings support integrating STR analysis into routine neurogenetic diagnostics.