LINKAGE ANALYSIS OF CANDIDATE LOCI IN AUTOSOMAL DOMINANT MYOTONIA-CONGENITA

Electrophysiologic studies in patients with autosomal dominant myotonia congenita (ADMC) have implicated defects of both muscle membrane sodium and chloride channels. An adult skeletal muscle sodium channel (ASkM1) gene maps to chromosome 17q23-25, and defects in this gene are almost certainly responsible for at least three variants of hyperkalemic periodic paralysis (HPP)-myotonic HPP, nonmyotonic HPP, and paramyotonia congenita. A gene for a muscle chloride channel has not yet been mapped in humans, but has been identified in the mouse. The gene for the cystic fibrosis transmembrane regulator (CFTR), which has chloride channel properties, is located on chromosome 7q31. This region is syntenic with the area of mouse chromosome 6 that contains the muscle chloride channel gene, a defect in which is responsible for the ADR phenotype, a murine model of myotonia. We performed linkage analysis using chromosome 17q polymorphisms at D17S74, SCN4A, and GH1, two chromosome 7q31 restriction fragment length polymorphisms, and a dinucleotide repeat polymorphism within the CFTR gene (CFTR-DNR), in three pedigrees with ADMC. The lod scores obtained show that the locus for ADMC is not at ASkM1 and is excluded from a region of at least 24 cM on either side of the CFTR gene.