Abstract Details

Title Mutations in KCND3 Cause Spinocerebellar Ataxia Type 22

Topic Movement Disorders

Presentation(s) IN6 - (-)

Poster/Presentation
Number 003

Objective

Background Previously, we characterized a large Chinese pedigree with an autosomal dominant ataxia spanning four generations. The disease locus was mapped to chromosome 1p21-q23 and was designated SCA22. The locus of SCA22 overlaps with that of SCA19 on 1p21-q21, previously identified in a Dutch family. SCA19 and SCA22 were therefore proposed to be allelic with a worldwide distribution.

Design/Methods The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to chromosome 1p21-q23. Members from all three families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and co-segregation 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 three-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 three mutations, c.1034G>T p.G345V, c.1013T>C p.V338E and c.1130C>T p.T377M, in three 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.

Conclusions Our data identified 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, key regulators of neuronal excitability, in the pathogenesis of cerebellar degeneration.

Authors/Disclosures
Bing-Wen Soong, MD, PhD, FAAN PRESENTER	No disclosure on file
Yi-Chung Lee, MD, FAAN (Taipei Veterans General Hospital)	The institution of Dr. Lee has received research support from National Science and technology Council Taiwan . The institution of Dr. Lee has received research support from Taipei Veterans General Hospital Taiwan.
Kathie M. Bishop, PhD	Dr. Bishop has received personal compensation for serving as an employee of Acadia Pharmaceuticals, Inc. . Dr. Bishop has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for DTx Pharma. Dr. Bishop has stock in Acadia Pharmaceuticals, Inc..

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