Frequency of KCNC3 DNA Variants as Causes of Spinocerebellar Ataxia 13 (SCA13)
Frequency of KCNC3 DNA Variants as Causes of Spinocerebellar Ataxia 13 (SCA13)
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DOI：
10.1371/journal.pone.0017811
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发表时间：
2011-03-29
期刊：
影响因子：
3.7
通讯作者：
Pulst, Stefan M.
中科院分区：
文献类型：
--
作者：
Figueroa, Karla P.;Waters, Michael F.;Pulst, Stefan M.
背景：电压门控钾通道KCNC3(Kv3.3)的功能获得或显性负突变是常染色体显性遗传性脊髓小脑性共济失调的原因。我们的目标是描述散发性或家族性共济失调患者中与KCNC3相关的突变频率。方法：对327例共济失调患者进行KCNC3基因编码区DNA序列分析。通过在非洲爪哇卵母细胞中表达DNA变异体来分析通道功能。主要发现：序列分析发现在外显子2中有两个非同义替换和五个内含子变化，这些变化没有被预测会改变剪接。我们在该通道的高度保守的S4结构域中发现了另一个P.Arg423His突变的家系。这个家庭有一例早发性疾病和相关的癫痫发作。第二个编码改变，p.Gly263Asp，微妙地改变了通道的生物物理特性，但不太可能与疾病相关，因为它发生在CACNA1a钙通道CAG重复序列扩大的个体中。结论：KCNC3突变是脊髓小脑性共济失调的罕见原因，频率低于1%。P.Arg423His突变在不同人群中反复发生，并与早发有关。与以前的p.Arg423His突变携带者不同，我们现在观察到一名个体出现癫痫发作和轻度精神发育迟滞。这项研究证实了SCA13具有广泛的表型谱。
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.