RT Journal Article
SR Electronic
T1 A novel missense mutation in <em>CCDC88C</em> activates the JNK pathway and causes a dominant form of spinocerebellar ataxia
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 590
OP 595
DO 10.1136/jmedgenet-2014-102333
VO 51
IS 9
A1 Ho Tsoi
A1 Allen C S Yu
A1 Zhefan S Chen
A1 Nelson K N Ng
A1 Anne Y Y Chan
A1 Liz Y P Yuen
A1 Jill M Abrigo
A1 Suk Ying Tsang
A1 Stephen K W Tsui
A1 Tony M F Tong
A1 Ivan F M Lo
A1 Stephen T S Lam
A1 Vincent C T Mok
A1 Lawrence K S Wong
A1 Jacky C K Ngo
A1 Kwok-Fai Lau
A1 Ting-Fung Chan
A1 H Y Edwin Chan
YR 2014
UL http://jmg.bmj.com/content/51/9/590.abstract
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.