MOLECULAR-GENETIC AND GENETIC CORRELATIONS IN SODIUM CHANNELOPATHIES - LACK OF FOUNDER EFFECT AND EVIDENCE FOR A 2ND GENE

We present a correlation of molecular genetic data (mutations) and gen etic data (dinucleotide-repeat polymorphisms) for a cohort of seven hy perkalemic periodic paralysis (HyperPP) and two paramyotonia congenita (PC) families from diverse ethnic backgrounds. We found that each of three previously identified point mutations of the adult skeletal musc le sodium-channel gene occurred on two different dinucleotide-repeat h aplotypes. These results indicate that dinucleotide-repeat haplotypes are not predictive of allelic heterogeneity in sodium channelopathies, contrary to previous suggestions. In addition, we identified a HyperP P pedigree in which the dominant disorder was not linked to the sodium -channel gene. Thus, a second locus can give rise to a similar clinica l phenotype. Some individuals in this pedigree exhibited a base change causing the nonconservative substitution of an evolutionarily conserv ed amino acid. Because this change was not present in 240 normal chrom osomes and was near another HyperPP mutation, it fulfilled the most co mmonly used criteria for being a mutation rather than a polymorphism. However, linkage studies using single-strand conformation polymorphism -derived and sequence-derived haplotypes excluded this base change as a causative mutation: these data serve as a cautionary example of pote ntial pitfalls in the delineation of change-of-function point mutation s.