Figueroa KP et al. (2011), Frequency of KCNC3 DNA variants as causes of sp...

XB-ART-43092

PLoS One 2011 Mar 29;63:e17811. doi: 10.1371/journal.pone.0017811.

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Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13).

Figueroa KP , Waters MF , Garibyan V , Bird TD , Gomez CM , Ranum LP , Minassian NA , Papazian DM , Pulst SM .

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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. METHODOLOGY: 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. PRINCIPAL FINDINGS: 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.

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Species referenced: Xenopus laevis
Genes referenced: cacna1a kcnc3

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	Figure 1. DNA electropherograms of a family with the p.Arg423His mutation.H2591shows the p.Arg423His mutation (arrow, top), her son (H2629) shows the p.Arg423His mutation and the c.1257C>A variant, and her daughter (H2630) shows the c.1257C>A change, but lacks the mutation.
	Figure 2. MRI of Patient with the p.Arg423His mutation.Cerebellar atrophy in a 48 year old female (H2591) with ataxia and the KCNC3Arg423His mutation. Midsagittal T1-weighted MRI of the brain shows a small atrophic cerebellum with a normal appearing brainstem.
	Figure 3. Mutation kinetics in X. laevis oocytes.p.Gly263Asp alters activation and deactivation kinetics in X. laevis oocytes. (A) p.Gly263Asp currents were evoked by stepping from −90 mV to voltages ranging from −90 mV to +70 mV in 10 mV increments. (B) Normalized isochronal tail current amplitudes have been plotted versus voltage for wild-type (▪, n = 84) and p.Gly263Asp (□, n = 8). (C) Activation time constant (τact) was plotted versus voltage. *Wild-type (▪, n = 36) and p.Gly263Asp (□, n = 8) values differed significantly , p<0.05. Inset: Wild-type (solid) and p.Gly263Asp (dotted) currents were evoked at 0 mV, scaled and overlaid. (D) Deactivation time constant (τdeact) was plotted versus repolarization voltage. Wild-type (▪, n = 10) and p.Gly263Asp (□, n = 8) values differed significantly, p<0.05. Inset: Wild-type (solid) and p.Gly263Asp (dotted) tail currents were recorded at −60 mV, scaled and overlaid.