Mapping of the hypokalaemic periodic paralysis (HypoPP) locus to chromosome 1q31–32 in three European families

Abstract

Hypokalaemic periodic paralysis (HypoPP) is an autosomal dominant muscle disease thought to arise from an abnormal function of ion channels. Performing a genome-wide search using polymorphic dinucleotide repeats, we have localized the HypoPP locus in three families of different geographic origin to chromosome 1q31-32, by linkage analysis. Using an intragenic microsatellite, we also demonstrate that the gene encoding the muscle DHP-sensitive calcium channel alpha 1 subunit (CACNL1A3) maps to the same region, sharing a 5 centiMorgan (cM) interval with the HypoPP locus. Moreover, CACNL1A3 co-segregates with HypoPP without recombinants in the two informative families, and is therefore a good candidate for the HypoPP gene.

Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current

“…Linkage analysis for exclusion of linkage to chromosome 1 (CACNA1S locus) and inclusion of chromosome 17 (SCN4A locus) was performed by using Généthon microsatellite markers, as previously described (18). For at least one patient of each family, all three known CACNA1S mutations were excluded by restriction analysis and single-strand conformation analysis (SSCA), as Abbreviations: HypoPP, hypokalemic periodic paralysis; HyperPP, hyperkalemic periodic paralysis; SCN4A, ␣ subunit of the adult skeletal muscle sodium channel; DHP, dihydropyridine; SSCA, single-strand conformation analysis; WT, wild type.…”

Electrophysiological properties of the hypokalaemic periodic paralysis mutation (R528H) of the skeletal muscle α1S subunit as expressed in mouse L cells

“…Linkage studies have shown that the HypoPP gene maps to chromosome lq31 32, and colocalizes with the gene encoding the cq subunit (CACNL1A3) of the skeletal muscle L-type Ca 2+ channel [1]. The L-type Ca 2+ channel in skeletal muscle is located in the membrane of transverse tubules and consists of five subunits, cq, c~2/8, [3 and 7.…”

Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis

“…Point mutations in CACNA1S or SCN4A, which encode the skeletal muscle voltage-gated calcium and sodium channels, associate with HypoPP. [1][2][3][4][5][6][7][8][9][10] However, in most studies at least 20% of cases remain genetically undefined. 8,11,12 Sodium and calcium channels have homologous pore-forming ␣ subunits, each containing four domains containing six transmembrane segments.…”