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

Spinocerebellar ataxias (SCAs) are a group of genetically diverse neurodegenerative disorders causing cerebellar degeneration and progressive ataxia. We identified an autosomal dominant SCA family (SCA40) which displays typical cerebellar ataxia signs and pontocerebellar atrophy. By performing whole-exome sequencing on multiple members of this family, we found a novel missense mutation in the gene CCDC88C in all affected individuals. Our cell-based assays showed that the SCA40 mutation causes an up-regulation of the JNK stress kinase signaling cascade that subsequently triggers programmed cell death. A similar cellular dysregulation was also observed in patient primary fibroblasts. Our work implicates that targeting JNK signaling and/or caspase cascades would be of therapeutic potential for treating SCA40. (By Dr. Edwin Chan, http://jmg.bmj.com/content/early/2014/07/25/jmedgenet-2014-102333 )