Dataset Information

A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia.

ABSTRACT: Spinocerebellar ataxias (SCAs) are a group of clinically and genetically diverse and autosomal-dominant disorders characterised by neurological deficits in the cerebellum. At present, there is no cure for SCAs. Of the different distinct subtypes of autosomal-dominant SCAs identified to date, causative genes for only a fraction of them are currently known. In this study, we investigated the cause of an autosomal-dominant SCA phenotype in a family that exhibits cerebellar ataxia and pontocerebellar atrophy along with a global reduction in brain volume.Whole-exome analysis revealed a missense mutation c.G1391A (p.R464H) in the coding region of the coiled-coil domain containing 88C (CCDC88C) gene in all affected individuals. Functional studies showed that the mutant form of CCDC88C activates the c-Jun N-terminal kinase (JNK) pathway, induces caspase 3 cleavage and triggers apoptosis.This study expands our understanding of the cause of autosomal-dominant SCAs, a group of heterogeneous congenital neurological conditions in humans, and unveils a link between the JNK stress pathway and cerebellar atrophy.

SUBMITTER: Tsoi H

PROVIDER: S-EPMC4145425 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia.

Tsoi Ho H Yu Allen C S AC Chen Zhefan S ZS Ng Nelson K N NK Chan Anne Y Y AY Yuen Liz Y P LY Abrigo Jill M JM Tsang Suk Ying SY Tsui Stephen K W SK Tong Tony M F TM Lo Ivan F M IF Lam Stephen T S ST Mok Vincent C T VC Wong Lawrence K S LK Ngo Jacky C K JC Lau Kwok-Fai KF Chan Ting-Fung TF Chan H Y Edwin HY

Journal of medical genetics 20140725 9

<h4>Background</h4>Spinocerebellar ataxias (SCAs) are a group of clinically and genetically diverse and autosomal-dominant disorders characterised by neurological deficits in the cerebellum. At present, there is no cure for SCAs. Of the different distinct subtypes of autosomal-dominant SCAs identified to date, causative genes for only a fraction of them are currently known. In this study, we investigated the cause of an autosomal-dominant SCA phenotype in a family that exhibits cerebellar ataxia ...[more]

PMID: 25062847

Similar Datasets

Project description:We undertook a gene identification and molecular characterization project in a large kindred originally clinically diagnosed with SCA-X1. While presenting with ataxia, this kindred also had some unique peripheral nervous system features. The implicated region on the X chromosome was delineated using haplotyping. Large deletions and duplications were excluded by array comparative genomic hybridization. Exome sequencing was undertaken in two affected subjects. The single identified X chromosome candidate variant was then confirmed to co-segregate appropriately in all affected, carrier and unaffected family members by Sanger sequencing. The variant was confirmed to be novel by comparison with dbSNP, and filtering for a minor allele frequency of <1% in 1000 Genomes project, and was not present in the NHLBI Exome Sequencing Project or a local database at the BCM HGSC. Functional experiments on transfected cells were subsequently undertaken to assess the biological effect of the variant in vitro. The variant identified consisted of a previously unidentified non-synonymous variant, GJB1 p.P58S, in the Connexin 32/Gap Junction Beta 1 gene. Segregation studies with Sanger sequencing confirmed the presence of the variant in all affected individuals and one known carrier, and the absence of the variant in unaffected members. Functional studies confirmed that the p.P58S variant reduced the number and size of gap junction plaques, but the conductance of the gap junctions was unaffected. Two X-linked ataxias have been associated with genetic loci, with the first of these recently characterized at the molecular level. This represents the second kindred with molecular characterization of X-linked ataxia, and is the first instance of a previously unreported GJB1 mutation with a dominant and permanent ataxia phenotype, although different CNS deficits have previously been reported. This pedigree has also been relatively unique in its phenotype due to the presence of central and peripheral neural abnormalities. Other X-linked SCAs with unique features might therefore also potentially represent variable phenotypic expression of other known neurological entities.

Dataset Information

A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia.

Publications

A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets