台灣團隊解開SCA22 (22型小腦萎縮症)成因: voltage-gated potassium channel Kv4.3-encoding gene KCND3

Mutations in KCND3 cause spinocerebellar ataxia type 22

Keywords: exome sequencing;next generation sequencing;spinocerebellar ataxia type 22;voltage-gated potassium channel;Kv4.3;KCND3

Objective: To identify the causative gene in SCA22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23.

Subjects and 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 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.

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. Ann Neurol 2012.

領先全球！榮陽團隊突破　找到第22型小腦萎縮症致病基因 陳鈞凱 2012年9月12日 16:59台北榮總與陽明大學腦科學研究中心攜手合作，領先全球，找出了第22型小腦萎縮症致病基因。 記者陳鈞凱／台北報導小腦萎縮症患者最怕一代傳一代，悲劇斷不了根！因為小腦萎縮症多達40多型，其中超過3成迄今找不出致病基因，不過最近，台北榮民總醫院神經醫學中心與陽明大學腦科學研究中心攜手合作，領先全球，找出了第22型小腦萎縮症致病基因，不但有利在產前、患者發病前提早篩檢，更替治療小腦萎縮症提供新方向。日劇「一公升的眼淚」、國片「帶一片風景走」，主角罹患小腦萎縮症的故事賺人熱淚，隨病程快慢，嚴重者可能喪失行動能力或無法坐立而臥床，盛行率約為每10萬人中有5至10人，可分為原因不明的散發型或遺傳型。82歲的林老先生，45歲起就有步履不穩的現象，平衡感不好，容易跌倒受傷，還逐漸出現說話咬字不夠清晰、喝水容易嗆到等症狀，卻直到60多歲才被確診出罹患第22型小腦萎縮症；家族三代人當中，目前也有接近10人出現類似症狀。代代相傳是小腦萎縮症病友的最大恐懼！小腦萎縮症病友協會理事長黃玉春說，全台目前約有2000多人罹患小腦萎縮症，加入協會病友約有400多人，在致病基因不明之下，有不少人發病後四處求神問卜、看風水改運，甚至自覺是上輩子被人下詛咒，還得面對顯性遺傳，一人發病、全家數代人跟著無藥可治的恐懼。