MAPPING OF A FURTHER MALIGNANT HYPERTHERMIA SUSCEPTIBILITY LOCUS TO CHROMOSOME 3Q13.1

Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic di sease for which MH susceptibility (MHS) is transmitted as an autosomal dominant trait. A potentially life-threatening MH crisis is triggered by exposure to commonly used inhalational anesthetics and depolarizin g muscle relaxants. The first malignant hyperthermia susceptibility lo cus (MHS1) was identified on human chromosome 19q13.1, and evidence ha s been obtained that defects in the gene for the calcium-release chann el of skeletal muscle sarcoplasmic reticulum (ryanodine receptor; RYR1 ) can cause some forms of MH. However, MH has been shown to be genetic ally heterogeneous, and additional loci on chromosomes 17q and 7q have been suggested. In a collaborative search of the human genome with po lymorphic microsatellite markers, we now found linkage of the MHS phen otype, as assessed by the European in vitro contracture test protocol, to markers defining a 1-cM interval on chromosome 3q13.1. A maximum m ultipoint led score of 3.22 was obtained in a single German pedigree w ith classical MH, and none of the other pedigrees investigated in this study showed linkage to this region. Linkage to both MHS1/RYR1 and pu tative loci on chromosome 17q and 7q were excluded. This study support s the view that considerable genetic heterogeneity exists in MH.