Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19
Version of Record online: 31 DEC 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 72, Issue 6, pages 870–880, December 2012
How to Cite
Duarri, A., Jezierska, J., Fokkens, M., Meijer, M., Schelhaas, H. J., den Dunnen, W. F. A., van Dijk, F., Verschuuren-Bemelmans, C., Hageman, G., van de Vlies, P., Küsters, B., van de Warrenburg, B. P., Kremer, B., Wijmenga, C., Sinke, R. J., Swertz, M. A., Kampinga, H. H., Boddeke, E. and Verbeek, D. S. (2012), Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Ann Neurol., 72: 870–880. doi: 10.1002/ana.23700
- Issue online: 31 DEC 2012
- Version of Record online: 31 DEC 2012
- Accepted manuscript online: 23 JUL 2012 06:29AM EST
- Manuscript Accepted: 13 JUN 2012
- Manuscript Revised: 21 MAY 2012
- Manuscript Received: 5 APR 2012
To identify the causative gene for the neurodegenerative disorder spinocerebellar ataxia type 19 (SCA19) located on chromosomal region 1p21-q21.
Exome sequencing was used to identify the causal mutation in a large SCA19 family. We then screened 230 ataxia families for mutations located in the same gene (KCND3, also known as Kv4.3) using high-resolution melting. SCA19 brain autopsy material was evaluated, and in vitro experiments using ectopic expression of wild-type and mutant Kv4.3 were used to study protein localization, stability, and channel activity by patch-clamping.
We detected a T352P mutation in the third extracellular loop of the voltage-gated potassium channel KCND3 that cosegregated with the disease phenotype in our original family. We identified 2 more novel missense mutations in the channel pore (M373I) and the S6 transmembrane domain (S390N) in 2 other ataxia families. T352P cerebellar autopsy material showed severe Purkinje cell degeneration, with abnormal intracellular accumulation and reduced protein levels of Kv4.3 in their soma. Ectopic expression of all mutant proteins in HeLa cells revealed retention in the endoplasmic reticulum and enhanced protein instability, in contrast to wild-type Kv4.3 that was localized on the plasma membrane. The regulatory β subunit Kv channel interacting protein 2 was able to rescue the membrane localization and the stability of 2 of the 3 mutant Kv4.3 complexes. However, this either did not restore the channel function of the membrane-located mutant Kv4.3 complexes or restored it only partially.
KCND3 mutations cause SCA19 by impaired protein maturation and/or reduced channel function. ANN NEUROL 2012;72:870–880