A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia.
J Med Genet
; 51(9): 590-5, 2014 Sep.
Article
in En
| MEDLINE
| ID: mdl-25062847
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 ANDRESULTS:
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.Key words
Full text:
1
Database:
MEDLINE
Main subject:
Mutation, Missense
/
Spinocerebellar Ataxias
/
MAP Kinase Signaling System
/
Intracellular Signaling Peptides and Proteins
/
Microfilament Proteins
Type of study:
Diagnostic_studies
/
Etiology_studies
/
Prognostic_studies
Limits:
Humans
/
Middle aged
Country/Region as subject:
Asia
Language:
En
Journal:
J Med Genet
Year:
2014
Type:
Article
Affiliation country:
Hong Kong