Localization of the malignant hyperthermia susceptibility locus to human chromosome 19ql2–13.2

Abstract

Malignant hyperthermia (MH) is an inherited human skeletal muscle disorder and is one of the main causes of death due to anaesthesia. The reported incidence of MH varies from 1 in 12,000 in children to 1 in 40,000 in adults. MH is triggered in susceptible people by all commonly used inhalational anaesthetics; it is characterized by a profoundly accelerated muscle metabolism, contractures, hyperthermia and tachycardia. Susceptibility to MH (MHS) is predicted by contracture tests on muscle tissue obtained by biopsy. An almost identical disorder known as porcine MH exists in pigs. The genetics of the porcine syndrome have been extensively studied; the locus controlling expression of porcine MH is genetically linked to the glucose phosphate isomerase locus (GPI). In man, GPI has been mapped to the q12-13.2 region of chromosome 19 (refs 10-12). We have now investigated genetic linkage in several extended Irish pedigrees in which MHS is segregating as an autosomal dominant trait. Here we show linkage between MHS and DNA markers from the GPI region of human chromosome 19 with a maximum log likelihood ratio (lod score) of 5.65 at the CYP2A locus. These results indicate that human and porcine MH are most probably due to mutations in homologous genes, and also provide a potentially accurate and noninvasive method of diagnosis for MHS.

Ca2+ signalling and muscle disease

“…Linkage between inheritance of MH and RYR1 markers or chromosome 19q markers, identified RYR1 as a candidate gene for MH in humans [36,37]. The discovery of several RYR1 mutations that could be linked to MH established RYR1 as a causal gene for MH.…”

B-lymphocytes from Malignant Hyperthermia-susceptible Patients Have an Increased Sensitivity to Skeletal Muscle Ryanodine Receptor Activators

“…The latter observation has led to the suggestion that MH, heat stroke, and exercise-induced rhabdomyolysis might have a common denominator (2,6,7). The underlying causes of MH are abnormalities in the skeletal muscle calcium metabolism (8,9) and molecular genetic studies have mapped the primary locus of MH to chromosome 19q, the gene encoding the ryanodine receptor calcium release channel (RYR1) (2,4,10). Approximately 50% of MH families have mutations in the RYR1 gene, and mutations have been reported in other loci (for recent reviews, see Refs.…”

Novel Mutations in C-terminal Channel Region of the Ryanodine Receptor in Malignant Hyperthermia Patients

“…Since MH is inherited as an autosomal dominant trait, causal mutations in the RyR1 gene (RYR1) have been investigated. Thus, MacLennan et al (10) and McCarthy et al (11) showed in their linkage study that the MH phenotype segregates with markers for RYR1 in the locus q13.1 of human chromosome 19. To date, twenty-six missense mutations (1 -3, 12 -16) in the cDNA of RyR1 have been identified among individuals having MH and /or the associated central core disease (CCD).…”