Genetic screening for potassium channel mutations in Japanese autosomal dominant spinocerebellar ataxia
Genetic screening for potassium channel mutations in Japanese autosomal dominant spinocerebellar ataxia
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DOI：
10.1038/s10038-019-0717-y
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发表时间：
2020-01-07
影响因子：
3.5
通讯作者：
Kawakami, Hideshi
中科院分区：
文献类型：
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作者：
Tada, Yui;Kume, Kodai;Kawakami, Hideshi
脊髓小脑性共济失调（SCA）是一种以小脑性共济失调为特征的遗传异质性疾病。目前已发现许多致病基因，其中最常见的是重复序列的异常扩增，离子通道基因的突变也在SCA的发生发展中起重要作用。其中一些编码钙和钾通道。然而，由于有关SCA中钾基因的报道有限，我们通过靶测序筛选了192名显性遗传SCA的日本个体，这些个体没有钾通道突变的致病基因（SCA 13的KCNC 3和SCA 19/SCA 22的KCND 3）的异常重复扩增。结果，从两名患者中鉴定出两种变体：KCNC 3的c.1973G>A，p.R658Q和c.1018G>A，p.V340M，并且未鉴定出KCND 3的致病性变体。新鉴定的p.V340M存在于细胞外结构域，p.R658Q存在于C-末端侧的细胞内结构域，尽管大多数报道的KCNC 3突变存在于跨膜位点。钾通道突变引起的SCA 13和SCA 19的主要临床特征是成人发作和缓慢进行性小脑共济失调，这在我们的病例中是相似的。由KCNC 3突变引起的SCA 13除了小脑性共济失调外，还可能表现为深度感觉丧失和认知障碍。在这项研究中，在1例病例中观察到轻度深部感觉丧失。钾离子通道基因突变引起的SCA极为罕见，今后应积累更多病例以阐明其因通道功能障碍引起的发病机制。
Spinocerebellar ataxia (SCA) is a genetically heterogeneous disease characterized by cerebellar ataxia. Many causative genes have been identified to date, the most common etiology being the abnormal expansion of repeat sequences, and the mutation of ion channel genes also play an important role in the development of SCA. Some of them encode calcium and potassium channels. However, due to limited reports about potassium genes in SCA, we screened 192 Japanese individuals with dominantly inherited SCA who had no abnormal repeat expansions of causative genes for potassium channel mutations (KCNC3 for SCA13 and KCND3 for SCA19/SCA22) by target sequencing. As a result, two variants were identified from two patients: c.1973G>A, p.R658Q and c.1018G>A, p.V340M for KCNC3, and no pathogenic variant was identified for KCND3. The newly identified p.V340M exists in the extracellular domain, and p.R658Q exists in the intracellular domain on the C-terminal side, although most of the reported KCNC3 mutations are present at the transmembrane site. Adult-onset and slowly progressive cerebellar ataxia are the main clinical features of SCA13 and SCA19 caused by potassium channel mutations, which was similar in our cases. SCA13 caused by KCNC3 mutations may present with deep sensory loss and cognitive impairment in addition to cerebellar ataxia. In this study, mild deep sensory loss was observed in one case. SCA caused by potassium channel gene mutations is extremely rare, and more cases should be accumulated in the future to elucidate its pathogenesis due to channel dysfunction.