title: Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13).
abstract: BACKGROUND
  Gain-of function or dominant-negative mutations in the voltage-gated potassium channel KCNC3 (Kv3.3) were recently identified as a cause of autosomal dominant spinocerebellar ataxia. Our objective was to describe the frequency of mutations associated with KCNC3 in a large cohort of index patients with sporadic or familial ataxia presenting to three US ataxia clinics at academic medical centers.
  
  
  METHODS
  DNA sequence analysis of the coding region of the KCNC3 gene was performed in 327 index cases with ataxia. Analysis of channel function was performed by expression of DNA variants in Xenopus oocytes.
  
  
  RESULTS
  Sequence analysis revealed two non-synonymous substitutions in exon 2 and five intronic changes, which were not predicted to alter splicing. We identified another pedigree with the p.Arg423His mutation in the highly conserved S4 domain of this channel. This family had an early-onset of disease and associated seizures in one individual. The second coding change, p.Gly263Asp, subtly altered biophysical properties of the channel, but was unlikely to be disease-associated as it occurred in an individual with an expansion of the CAG repeat in the CACNA1A calcium channel.
  
  
  CONCLUSIONS
  Mutations in KCNC3 are a rare cause of spinocerebellar ataxia with a frequency of less than 1%. The p.Arg423His mutation is recurrent in different populations and associated with early onset. In contrast to previous p.Arg423His mutation carriers, we now observed seizures and mild mental retardation in one individual. This study confirms the wide phenotypic spectrum in SCA13.
authors.affiliation: Department of Neurology, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Karla P
authors.initials: KP
authors.lastname: Figueroa
authors.forename: Michael F
authors.initials: MF
authors.lastname: Waters
authors.forename: Vartan
authors.initials: V
authors.lastname: Garibyan
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bird
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Gomez
authors.forename: Laura P W
authors.initials: LP
authors.lastname: Ranum
authors.forename: Natali A
authors.initials: NA
authors.lastname: Minassian
authors.forename: Diane M
authors.initials: DM
authors.lastname: Papazian
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pulst
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D006801:Humans; D007700:Kinetics; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009865:Oocytes / Q000378:metabolism; D010641:Phenotype; D051670:Shaw Potassium Channels / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000235:genetics; D014982:Xenopus laevis
chemical_list: C489594:KCNC3 protein, human; D051670:Shaw Potassium Channels; D004247:DNA