Identification of mutations including de novo mutations in Korean patients with hypokalaemic periodic paralysis

Background. 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 α₁-subunit (CACNAIS). So far, three different mutations in CACNAIS gene have been identified in patients with hypoPP: Arg528His, Arg1239His and Arg1239Gly in Caucasian patients. However, there are few reports about the mutations of CACNAIS gene in other races. Methods. In this study, four Korean families with five hypoPP patients were screened for mutations of CACNAIS 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 (DIS1726, CACNL1A3, and DIS1723). Results. 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 (DIS1726, CACNLIA3, and DIS1723) suggested the occurrence of de novo Arg528His mutations in two of the three families with Arg528His mutation. Conclusions. 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.