Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.
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ABSTRACT:
SUBMITTER: Darwich NF
PROVIDER: S-EPMC7818661 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau
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Project description:BACKGROUND:Nemaline myopathy (NEM) is one of the three major forms of congenital myopathy and is characterized by diffuse muscle weakness, hypotonia, respiratory insufficiency, and the presence of nemaline rod structures on muscle biopsy. Mutations in troponin T1 (TNNT1) is 1 of 10 genes known to cause NEM. To date, only homozygous nonsense mutations or compound heterozygous truncating or internal deletion mutations in TNNT1 gene have been identified in NEM. This extended family is of historical importance as some members were reported in the 1960s as initial evidence that NEM is a hereditary disorder. METHODS:Proband and extended family underwent Sanger sequencing for TNNT1. We performed RT-PCR and immunoblot on muscle to assess TNNT1 RNA expression and protein levels in proband and father. RESULTS:We report a novel heterozygous missense mutation of TNNT1 c.311A>T (p.E104V) that segregated in an autosomal dominant fashion in a large family residing in the United States. Extensive sequencing of the other known genes for NEM failed to identify any other mutant alleles. Muscle biopsies revealed a characteristic pattern of nemaline rods and severe myofiber hypotrophy that was almost entirely restricted to the type 1 fiber population. CONCLUSION:This novel mutation alters a residue that is highly conserved among vertebrates. This report highlights not only a family with autosomal dominant inheritance of NEM, but that this novel mutation likely acts via a dominant negative mechanism.
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Project description:Background:Congenital cataracts is the most common cause of childhood visual impairment and blindness worldwide. It is reported that about one quarter of congenital cataracts caused by genetic defects. Various gene mutations have been identified in hereditary cataracts so far. The purpose of the present study was to investigate the relationship between gap junction protein alpha 8 (GJA8) gene mutation and congenital cataract. Methods:A pedigree with autosomal dominant congenital cataract was investigated and the peripheral venous blood was extracted from 18 family members. After the high-throughput targeted capture and whole exome sequencing for the proband, bioinformatics analysis was performed. By combining the proband clinical symptoms, candidate variations were eliminated which were significantly not consistent with the clinical phenotype. And disease-causing variant was identified. Results:Gene sequencing revealed the heterozygous missense mutation in exon 2 of the GJA8 gene (c.178G>A), which co-segregated with the disease phenotype in the family and resulted in the substitution of glycine to serine at position 178 (p.G60S). This missense mutation was located in the hotspot mutation region, and might be harmful. Conclusions:This study reports a novel disease-causing sequence variant in the gap junctional protein encoding genes causing autosomal dominant congenital cataract in the Chinese population, caused by the missense mutation of GJA8 (c.178G>A). Our data expand the spectrum of GJA8 variants and associated phenotypes, facilitate clinical diagnosis and support the presence of relationship between genetic basis and human disease.
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Project description:Apolipoprotein E 4 Allele (APOE 4) is an important factors in Mild cognitive impairment (MCI) and Alzheimer's disease(AD). It plays a primary role in abnormal modification of aggregated Tau protein-paired helical filaments Tau (PHF-Tau). In this study, 143 subjects with PHF-Tau PET were divided into 2 groups (APOE 4 carriers and noncarriers). The measurements of the PHF-Tau network properties and resilient were calculated for 2 group networks respectively. APOE 4 carriers group showed significant differences in all the network properties in the results. We also found significant differences of betweenness centrality in some brain regions for APOE 4 carriers. Moreover, the APOE 4 carriers showed less resilient to targeted or random node failure. Our results indicated that the effects of APOE 4 may lead to abnormalities of PHF-Tau protein network. These findings may be particularly helpful in uncovering the pathophysiology underlying the cognitive dysfunction in MCI patients.
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Project description:IMPORTANCE:The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients. OBJECTIVE:To identify the genetic cause for a novel form of pure autosomal dominant HSP. DESIGN, SETTING, AND PARTICIPANTS:We examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened. MAIN OUTCOME AND MEASURE:Mutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene. RESULTS:We identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P <?.01) and size (0.29 [0.01] vs 0.26 [0.01]; P <?.05) of lipid droplets on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1c-/- mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; P <?.001), suggesting a dominant negative mechanism for the mutation. CONCLUSIONS AND RELEVANCE:This study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis.
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Project description:Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%-50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D.
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