Kim S H, Kim U K, Chae J J, Kim D J, Oh H Y, Kim B J, Lee C C
Department of Biology and SRC for Cell Differentiation, Seoul National University, Seoul, Korea.
Nephrol Dial Transplant. 2001 May;16(5):939-44. doi: 10.1093/ndt/16.5.939.
Hypokalaemic periodic paralysis (hypoPP) is an autosomal dominant disorder involving the abnormal function of ion channels and it is characterized by paralysis attacks of varying severity, accompanied by a fall in blood potassium levels. Linkage analysis showed that the candidate locus responsible for hypoPP was localized to chromosome 1q31-32, and this locus encoded the muscle dihydropyridine-sensitive calcium channel alpha(1)-subunit (CACNA1S). So far, three different mutations in CACNA1S gene have been identified in patients with hypoPP: Arg528His, Arg1239His and Arg1239Gly in Caucasian patients. However, there are few reports about the mutations of CACNA1S gene in other races.
In this study, four Korean families with five hypoPP patients were screened for mutations of CACNA1S gene with polymerase chain reaction-based restriction analysis and single-strand conformation polymorphism analysis. To determine the mode of inheritance, haplotype analysis was done with three microsatellite markers (D1S1726, CACNL1A3, and D1S1723).
Arg528His mutation was detected in three families, and one family had no known mutations. Moreover, for the first time, we detected de novo Arg528His mutations in two out of three families with hypoPP. Haplotype analysis using three microsatellite markers (D1S1726, CACNL1A3, and D1S1723) suggested the occurrence of de novo Arg528His mutations in two of the three families with Arg528His mutation.
Arg528His mutations of CACNA1S, including de novo Arg528His mutations, were found in Korean patients with hypoPP. These results imply that de novo mutation, in addition to non-penetrance, is one of the genetic mechanisms that can explain the previous clinical observation that hypoPP occurs sporadically without family history.
低钾性周期性麻痹（hypoPP）是一种常染色体显性疾病，涉及离子通道功能异常，其特征为不同严重程度的麻痹发作，并伴有血钾水平下降。连锁分析表明，导致hypoPP的候选基因座定位于1q31 - 32染色体，该基因座编码肌肉二氢吡啶敏感性钙通道α(1)-亚基（CACNA1S）。到目前为止，在hypoPP患者中已鉴定出CACNA1S基因的三种不同突变：白种人患者中的Arg528His、Arg1239His和Arg1239Gly。然而，关于其他种族中CACNA1S基因突变的报道很少。
在本研究中，对四个有五名hypoPP患者的韩国家庭进行了筛查，采用基于聚合酶链反应的限制性分析和单链构象多态性分析来检测CACNA1S基因的突变。为确定遗传方式，使用三个微卫星标记（D1S1726、CACNL1A3和D1S1723）进行单倍型分析。
在三个家庭中检测到Arg528His突变，一个家庭未发现已知突变。此外，我们首次在三个患有hypoPP的家庭中的两个家庭中检测到新生的Arg528His突变。使用三个微卫星标记（D1S1726、CACNL1A3和D1S1723）进行的单倍型分析表明，在三个发生Arg528His突变的家庭中的两个家庭中出现了新生的Arg528His突变。
在韩国hypoPP患者中发现了CACNA1S基因的Arg528His突变，包括新生的Arg528His突变。这些结果表明，除了基因不穿透性外，新生突变是一种遗传机制，可解释先前的临床观察结果，即hypoPP可在无家族史的情况下散发性发生。
