Integrating eQTL and GWAS data characterises established and identifies novel migraine risk loci
AbstractMigraine —a painful, throbbing headache disorder—is the most common complex brain disorder, yet its molecular mechanisms remain unclear. Genome-wide association studies (GWAS) have proven successful in identifying migraine risk loci; however, much work remains to identify the causal variants and genes. I n this paper, we compared three transcriptome-wide association study (TWAS) imputation models—MASHR, elastic net, and SMultiXcan—to characterise established genome-wide significant (GWS) migraine GWAS risk loci, and to identify putative novel migraine risk gene loci. We compared the standard TWA S approach ...
Source: Human Genetics - May 28, 2023 Category: Genetics & Stem Cells Source Type: research
A loss-of-function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia
In this study, we present a Miniature Australian Shepherd family showing clinical signs, which have genetic and phenotypic similarities with human hereditary hyperekplexia: episodes of muscle stiffness that could occasionally be triggered by acoustic stimuli. Whole genome sequence data analysis of two affected dogs revealed a 36-bp deletion spanning the exon –intron boundary in the glycine receptor alpha 1 (GLRA1) gene. Further validation in pedigree samples and an additional cohort of 127 Miniature Australian Shepherds, 45 Miniature American Shepherds and 74 Australian Shepherds demonstrated complete segregation of the ...
Source: Human Genetics - May 24, 2023 Category: Genetics & Stem Cells Source Type: research
Spinocerebellar ataxia 38: structure –function analysis shows ELOVL5 G230V is proteotoxic, conformationally altered and a mutational hotspot
AbstractFatty acid elongase ELOVL5 is part of a protein family of multipass transmembrane proteins that reside in the endoplasmic reticulum where they regulate long-chain fatty acid elongation. A missense variant (c.689G>T p.Gly230Val) inELOVL5 causes Spinocerebellar Ataxia subtype 38 (SCA38), a neurodegenerative disorder characterized by autosomal dominant inheritance, cerebellar Purkinje cell demise and adult-onset ataxia. Having previously showed aberrant accumulation of p.G230V in the Golgi complex, here we further investigated the pathogenic mechanisms triggered by p.G230V, integrating functional studies with bioin...
Source: Human Genetics - May 18, 2023 Category: Genetics & Stem Cells Source Type: research
De novo MCM6 variants in neurodevelopmental disorders: a recognizable phenotype related to zinc binding residues
AbstractThe minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier –Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes co...
Source: Human Genetics - May 17, 2023 Category: Genetics & Stem Cells Source Type: research
Proteomic profiling of retina and retinal pigment epithelium combined embryonic tissue to facilitate ocular disease gene discovery
AbstractTo expedite gene discovery in eye development and its associated defects, we previously developed a bioinformatics resource-tool iSyTE (integrated Systems Tool for Eye gene discovery). However, iSyTE is presently limited to lens tissue and is predominantly based on transcriptomics datasets. Therefore, to extend iSyTE to other eye tissues on the proteome level, we performed high-throughput tandem mass spectrometry (MS/MS) on mouse embryonic day (E)14.5 retina and retinal pigment epithelium combined tissue and identified an average of 3300 proteins per sample (n = 5). High-throughput expression profiling-based ge...
Source: Human Genetics - May 16, 2023 Category: Genetics & Stem Cells Source Type: research
Genotype –phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder
We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20)CNTNAP2 variants and carried out a literature review to characterize the genotype –phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsych...
Source: Human Genetics - May 14, 2023 Category: Genetics & Stem Cells Source Type: research
Deficiency of the mitochondrial ribosomal subunit, MRPL50, causes autosomal recessive syndromic premature ovarian insufficiency
In conclusion, we have shown that aMRPL50 missense variant destabilises the mitochondrial ribosome, leading to oxidative phosphorylation deficiency and syndromic POI, highlighting the importance of mitochondrial support in ovarian development and function. (Source: Human Genetics)
Source: Human Genetics - May 6, 2023 Category: Genetics & Stem Cells Source Type: research
