Dataset Information

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

ABSTRACT:

Background

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.

Methods and results

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.

Conclusions

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

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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

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Project description:This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes, which has not been depicted by the known neurodegenerative disease. We performed physical and neurological examinations with International Rating Scales to assess signs of ataxia, Parkinsonism, and cognitive function, as well as brain magnetic resonance imaging scans with seven sequences. We searched for co-segregations of abnormal repeat-expansion loci, pathogenic variants in known spinocerebellar ataxia-related genes, and novel rare mutations via whole-genome sequencing and linkage analysis. A rare co-segregating missense mutation in the CARS gene was validated by Sanger sequencing and the aminoacylation activity of mutant CARS was measured by spectrophotometric assay. This pedigree presented novel late-onset core characteristics including cerebellar ataxia, Parkinsonism, and pyramidal signs in all nine affected members. Brain magnetic resonance imaging showed cerebellar/pons atrophy, pontine-midline linear hyperintensity, decreased rCBF in the bilateral basal ganglia and cerebellar dentate nucleus, and hypo-intensities of the cerebellar dentate nuclei, basal ganglia, mesencephalic red nuclei, and substantia nigra, all of which suggested neurodegeneration. Whole-genome sequencing identified a novel pathogenic heterozygous mutation (E795V) in the CARS gene, meanwhile, exhibited none of the known repeat-expansions or point mutations in pathogenic genes. Remarkably, this CARS mutation causes a 20% decrease in aminoacylation activity to charge tRNACys with L-cysteine in protein synthesis compared with that of the wild type. All family members carrying a heterozygous mutation CARS (E795V) had the same clinical manifestations and neuropathological changes of Parkinsonism and spinocerebellar-ataxia. These findings identify novel pathogenesis of Parkinsonism-spinocerebellar ataxia and provide insights into its genetic architecture.

Dataset Information

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

Background

Methods and results

Conclusions

Publications

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

Similar Datasets

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