Genetic mapping of the beta 1- and gamma-subunits of the human skeletal muscle L-type voltage-dependent calcium channel on chromosome 17q and exclusion as candidate genes for malignant hyperthermia susceptibility.

Abstract

Malignant hyperthermia susceptibility (MHS) is an autosomal dominant disorder of skeletal muscle which manifests as a life-threatening hypermetabolic crisis triggered by commonly-used inhalation anaesthetics and depolarizing muscle relaxants. Defects in the ryanodine receptor (RYR1) protein have been proposed to underly MHS, but significant genetic heterogeneity in MHS has recently been demonstrated. In order to investigate the potential roles played by other skeletal muscle calcium channels in MHS, we isolated cosmids containing the gene encoding the beta 1-subunit of skeletal muscle L-type voltage-dependent calcium channel (CACNLB1). We identified a new, highly polymorphic dinucleotide repeat motif close to this gene, and linkage analysis placed the marker proximal to the HOX2B locus, previously localized to chromosome segment 17q21-q22. We recently identified a novel marker within the gamma-subunit locus (CACNLG) at band 17q24, and since both markers are within the 17q11.2-q24 region reported to contain the MHS2 locus, we tested them for linkage in MHS families whose disease trait has been shown not to co-segregate with markers for the RYR1 region on chromosome 19q13.1. Our results exclude CACNLB1 and CACNLG as candidate genes for MHS2, and do not support the reported chromosome 17q localization for the MHS2 locus in our families.