Mutations in KCND3 cause spinocerebellar ataxia type 22.
Mutations in KCND3 cause spinocerebellar ataxia type 22.
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DOI：
10.1002/ana.23701
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发表时间：
2012-12
影响因子：
11.2
通讯作者：
Soong, Bing-Wen
中科院分区：
文献类型：
--
作者：
Lee, Yi-Chung;Durr, Alexandra;Majczenko, Karen;Huang, Yen-Hua;Liu, Yu-Chao;Lien, Cheng-Chang;Tsai, Pei-Chien;Ichikawa, Yaeko;Goto, Jun;Monin, Marie-Lorraine;Li, Jun Z.;Chung, Ming-Yi;Mundwiller, Emeline;Shakkottai, Vikram;Liu, Tze-Tze;Tesson, Christelle;Lu, Yi-Chun;Brice, Alexis;Tsuji, Shoji;Burmeister, Margit;Stevanin, Giovanni;Soong, Bing-Wen
为了鉴定SCA22的致病基因，将常染色体显性小脑性共济失调定位到染色体1p21-q23上。我们之前描述了一个具有进行性共济失调的中国大家族，命名为SCA22，它与SCA19的位点重叠。一个法国家庭和一个德系犹太人美国家庭的疾病位点也被定位到该地区。三个家庭的成员都被录取了。全外显子组测序鉴定候选突变，通过连锁分析缩小候选突变范围，并通过Sanger测序和共分离分析确认候选突变。对105个中国和55个日本小脑性共济失调家族进行了突变分析。在异源表达系统中检测突变基因产物，以解决蛋白质定位和电生理功能的变化。我们在电压门控钾通道kv4.3编码基因KCND3中发现了杂合突变：在中国和法国家系中发现了帧内三核苷酸缺失的c.679_681delTTC p.F227del，在德系犹太家庭中发现了c.1034G>T p.G345V错义突变。KCND3的直接测序进一步鉴定了三个突变，C . 1034g >T p.G345V, C . 1013t >C . v338e和C . 1130c >T p.T377M，在三个日本品种中。免疫荧光分析显示，突变体p.F227del Kv4.3亚基保留在细胞质中，与全细胞膜片钳记录中缺乏a型K+通道电导一致。我们的数据确定不同种族的患者sc19 /22的病因是KCND3突变。这些发现进一步强调了离子通道作为神经元兴奋性的关键调节因子在小脑变性发病机制中的重要作用。
To identify the causative gene in SCA22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23. 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. 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. 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.
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影响因子：
14.5
作者：
Chung, MY;Lu, YC;Soong, BW
通讯作者：
Soong, BW
影响因子：
3.4
作者：
Hsu, YH;Huang, HY;Tsaur, ML
通讯作者：
Tsaur, ML
影响因子：
3.7
作者：
Figueroa, Karla P.;Waters, Michael F.;Pulst, Stefan M.
通讯作者：
Pulst, Stefan M.
DOI：
10.1152/ajpheart.1998.275.6.h1963
发表时间：
1998-12-01
影响因子：
4.8
作者：
Kong, W;Po, S;Tomaselli, GF
通讯作者：
Tomaselli, GF
影响因子：
9.9
作者：
Lee, Y. C.;Yu, C. T. R.;Soong, B. W.
通讯作者：
Soong, B. W.