Mutations in KCND3 cause spinocerebellar ataxia type 22.
Ann Neurol.. 2012-12-01; 72(6): 859-869
DOI: 10.1002/ana.23701
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1. Ann Neurol. 2012 Dec;72(6):859-69. doi: 10.1002/ana.23701.
Mutations in KCND3 cause spinocerebellar ataxia type 22.
Lee YC(1), Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, Tsai PC, Ichikawa Y,
Goto J, Monin ML, Li JZ, Chung MY, Mundwiller E, Shakkottai V, Liu TT, Tesson C,
Lu YC, Brice A, Tsuji S, Burmeister M, Stevanin G, Soong BW.
Author information:
(1)Department of Neurology, National Yang-Ming University School of Medicine,
Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei,
Taiwan.
Comment in
Nat Rev Neurol. 2012 Sep;8(9):472.
Ann Neurol. 2012 Dec;72(6):829-31.
OBJECTIVE: To identify the causative gene in spinocerebellar ataxia (SCA) 22, an
autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23.
METHODS: 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.
RESULTS: 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.
INTERPRETATION: 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.
Copyright © 2012 American Neurological Association.
DOI: 10.1002/ana.23701
PMCID: PMC4085146
PMID: 23280837 [Indexed for MEDLINE]