HYPOKALEMIC PERIODIC PARALYSIS AND THE DIHYDROPYRIDINE RECEPTOR (CACNLIA3) - GENOTYPE-PHENOTYPE CORRELATIONS FOR 2 PREDOMINANT MUTATIONS AND EVIDENCE FOR THE ABSENCE OF A FOUNDER EFFECT IN 16 CAUCASIAN FAMILIES

Hypokalemic periodic paralysis (hypoPP) is an autosomal dominant disor der belonging to a group of muscle diseases involving the abnormal fun ction of ion channels. This group of muscle diseases also comprises hy perkalemic periodic paralysis and paramyotonia congenita, both sodium- channel diseases, and myotonia congenita, a chloride-channel disorder. HypoPP is characterized by acute attacks of muscle weakness concomita nt with a fall in blood potassium levels. We recently localized the hy poPP locus (hypoPP1) to chromosome 1q31-32, in an interval where the a lpha 1 subunit of the dihydropyridine receptor calcium channel (CACNL1 A3) also maps. Subsequently, deleterious mutations in the voltage-sens or segment S4 were found, establishing the dihydropyridine receptor CA CNL1A3 as the causative gene for hypoPP. In this paper, we report the study of 16 hypoPP families of Caucasian origin. found only two mutati ons-Arg528His and Arg1239His-that cosegregated with hypoPP, each in ha lf of the families. Analysis of the clinical characteristics of both g roups of families demonstrated that incomplete penetrance is a distinc tive feature of the Arg528His mutation. Using dinucleotide repeats con tained within or close to the dihydropyridine receptor gene, in conjun ction with evidence of a de novo Arg1239His mutation, we show that a f ounder effect is unlikely to account for the two predominant mutations .