Mutations in KCND3 cause spinocerebellar ataxia type 22
Version of Record online: 31 DEC 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 72, Issue 6, pages 859–869, December 2012
How to Cite
Lee, Y.-C., Durr, A., Majczenko, K., Huang, Y.-H., Liu, Y.-C., Lien, C.-C., Tsai, P.-C., Ichikawa, Y., Goto, J., Monin, M.-L., Li, J. Z., Chung, M.-Y., Mundwiller, E., Shakkottai, V., Liu, T.-T., Tesson, C., Lu, Y.-C., Brice, A., Tsuji, S., Burmeister, M., Stevanin, G. and Soong, B.-W. (2012), Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol., 72: 859–869. doi: 10.1002/ana.23701
- Issue online: 31 DEC 2012
- Version of Record online: 31 DEC 2012
- Accepted manuscript online: 23 JUL 2012 06:29AM EST
- Manuscript Accepted: 16 JUL 2012
- Manuscript Revised: 12 JUL 2012
- Manuscript Received: 9 MAR 2012
To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23.
We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions.
We identified heterozygous mutations in the voltage-gated potassium channel Kv4.3-encoding gene KCND3: an in-frame 3-nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034G>T p.G345V, c.1013T>C p.V338E, and c.1130C>T p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A-type K+ channel conductance in whole cell patch-clamp recordings.
Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration. ANN NEUROL 2012;72:859–869.