RYANODINE RECEPTOR GENE IS A CANDIDATE FOR PREDISPOSITION TO MALIGNANT HYPERTHERMIA

MALIGNANT hyperthermia (MH) is a potentially lethal condition in which sustained muscle contracture, with attendant hypercatabolic reactions and elevation in body temperature, are triggered by commonly used inhalational anaesthetics and skeletal muscle relaxants1. In humans, the trait is usually inherited in an autosomal dominant fashion2, but in halothane-sensitive pigs3with a similar phenotype, inheritance of the disease is autosomal recessive or co-dominant. A simple and accurate non-invasive test for the gene is not available and predisposition to the disease is currently determined through a halothane- and/or caffeine-induced contracture test on a skeletal muscle biopsy4,5. Because Ca2+ is the chief regulator of muscle contraction and metabolism, the primary defect in MH is believed to lie in Ca2+ regulation1,6. Indeed, several studies indicate a defect in the Ca2+ release channel of the sarcoplasmic reticulum7-12, making it a ′ candidate for the altered gene product in predisposed individuals. We have recently cloned complementary DNA and genomic DNA encoding the human ryanodine receptor13 (the Ca2+-release channel of the sarcoplasmic reticulum) and mapped the ryanodine receptor gene(RYR) to region q13.1 of human chromosome 19 (ref. 14), in close proximity to genetic markers that have been shown to map near the MH susceptibility locus in humans15 and the halothane-sensitive gene in pigs16. As a more definitive test of whether the RYR gene is a candidate gene for the human MH phenotype, we have carried out a linkage study with MH families to determine whether the MH phenotype segregates with chromosome 19q markers, including markers in the RYR gene. Co-segregation of MH with RYRmarkers, resulting in a lod score of 4.20 at a linkage distance of zero centimorgans, indicates that MH is likely to be caused by mutations in the RYR gene. © 1990 Nature Publishing Group.