PT  - JOURNAL ARTICLE
AU  - Ho Tsoi
AU  - Allen C S Yu
AU  - Zhefan S Chen
AU  - Nelson K N Ng
AU  - Anne Y Y Chan
AU  - Liz Y P Yuen
AU  - Jill M Abrigo
AU  - Suk Ying Tsang
AU  - Stephen K W Tsui
AU  - Tony M F Tong
AU  - Ivan F M Lo
AU  - Stephen T S Lam
AU  - Vincent C T Mok
AU  - Lawrence K S Wong
AU  - Jacky C K Ngo
AU  - Kwok-Fai Lau
AU  - Ting-Fung Chan
AU  - H Y Edwin Chan
TI  - A novel missense mutation in <em>CCDC88C</em> activates the JNK pathway and causes a dominant form of spinocerebellar ataxia
AID  - 10.1136/jmedgenet-2014-102333
DP  - 2014 Sep 01
TA  - Journal of Medical Genetics
PG  - 590--595
VI  - 51
IP  - 9
4099  - http://jmg.bmj.com/content/51/9/590.short
4100  - http://jmg.bmj.com/content/51/9/590.full
SO  - J Med Genet2014 Sep 01; 51
AB  - 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.