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

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

  • J Med Genet. 2014 Sep;51(9):590-5. doi: 10.1136/jmedgenet-2014-102333.
Ho Tsoi 1,  Allen C S Yu 2,  Zhefan S Chen 1,  Nelson K N Ng 1,  Anne Y Y Chan 3,  Liz Y P Yuen 4,  Jill M Abrigo 5,  Suk Ying Tsang 6,  Stephen K W Tsui 7,  Tony M F Tong 8,  Ivan F M Lo 8,  Stephen T S Lam 8,  Vincent C T Mok 3,  Lawrence K S Wong 3,  Jacky C K Ngo 2,  Kwok-Fai Lau 2,  Ting-Fung Chan 6,  H Y Edwin Chan 1
Affiliations

Affiliations

  • 1 Faculty of Science, Laboratory of Drosophila Research, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
  • 2 Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
  • 3 Faculty of Medicine, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
  • 4 Faculty of Medicine, Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
  • 5 Faculty of Medicine, Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
  • 6 Faculty of Science, Biochemistry Programme, School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong Partner State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong.
  • 7 Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
  • 8 Clinical Genetic Service, Department of Health, The Government of Hong Kong, Hong Kong, Hong Kong.
PMID: 25062847 DOI: 10.1136/jmedgenet-2014-102333
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.

Keywords

Clinical Genetics; Neurology.

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