Wang Qiufen, Liu Mugen, Xu Chunsheng, Tang Zhaohui, Liao Yuhua, Du Rong, Li Wei, Wu Xiaoyan, Wang Xu, Liu Ping, Zhang Xianqin, Zhu Jianfang, Ren Xiang, Ke Tie, Wang Qing, Yang Junguo
Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China.
J Mol Med (Berl). 2005 Mar;83(3):203-8. doi: 10.1007/s00109-005-0638-4. Epub 2005 Feb 22.
Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disorder which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. The skeletal muscle calcium channel alpha-subunit gene CACNA1S is a major disease-causing gene for HypoPP, however, only three specific HypoPP-causing mutations, Arg528His, Arg1,239His and Arg1,239Gly, have been identified in CACNA1S to date. In this study, we studied a four-generation Chinese family with HypoPP with 43 living members and 19 affected individuals. Linkage analysis showed that the causative mutation in the family is linked to the CACNA1S gene with a LOD score of 6.7. DNA sequence analysis revealed a heterozygous C to G transition at nucleotide 1,582, resulting in a novel 1,582C-->G (Arg528Gly) mutation. The Arg528Gly mutation co-segregated with all affected individuals in the family, and was not present in 200 matched normal controls. The penetrance of the Arg528Gly mutation was complete in male mutation carriers, however, a reduced penetrance of 83% (10/12) was observed in female carriers. No differences were detected for age-at-onset and severity of the disease (frequency of symptomatic attacks per year) between male and female patients. Oral intake of KCl is effective in blocking the symptomatic attacks. This study identifies a novel Arg528Gly mutation in the CACNA1S gene that causes HypoPP in a Chinese family, expands the spectrum of mutations causing HypoPP, and demonstrates a gender difference in the penetrance of the disease.
低钾性周期性麻痹（HypoPP）是一种常染色体显性疾病，其特征为与血清钾水平降低相关的周期性肌无力发作。骨骼肌钙通道α亚基基因CACNA1S是HypoPP的主要致病基因，然而，迄今为止在CACNA1S中仅鉴定出三种特定的导致HypoPP的突变，即Arg528His、Arg1239His和Arg1239Gly。在本研究中，我们对一个四代中国HypoPP家族进行了研究，该家族有43名在世成员，其中19人患病。连锁分析表明，该家族中的致病突变与CACNA1S基因连锁，LOD评分为6.7。DNA序列分析显示，在核苷酸1582处发生了杂合的C到G转换，导致一个新的1582C→G（Arg528Gly）突变。Arg528Gly突变与该家族所有患病个体共分离，且在200名匹配的正常对照中未出现。Arg528Gly突变在男性突变携带者中的外显率是完全的，然而，在女性携带者中观察到外显率降低，为83%（10/12）。在男性和女性患者之间，未检测到发病年龄和疾病严重程度（每年症状发作频率）的差异。口服氯化钾可有效阻止症状发作。本研究在一个中国家族中鉴定出一种导致HypoPP的CACNA1S基因新突变Arg528Gly，扩大了导致HypoPP的突变谱，并证明了该疾病在外显率上存在性别差异。
