Genetic Mutation Characterized in Malignant Hyperthermia Canine Population

Abstract

Genetic Mutation Characterized in Malignant Hyperthermia Canine Population. Roberts et al. (page 716)In pigs and in up to 50% of humans who experience malignant hyperthermia (MH) events, the disorder has been linked to mutations in the calcium release channel of the sarcoplasmic reticulum, also known as the ryanodine receptor 1 (RyR1). To determine the molecular basis of canine MH, Roberts et al. established a breeding colony by mating a male mixed-breed dog that was MH-susceptible (MHS) and had survived an in vivo halothane–succinylcholine challenge to three unaffected females, producing four litters. Two additional litters were produced by back-crossing to an unaffected daughter and by mating an MHS son to an unaffected female. Of the total of 47 dogs produced from this breeding program, 31 were subjected to a halothane–succinylcholine challenge in an effort to trigger an MH event. The researchers also biopsied specimens of gracilis muscle obtained from all 47 dogs to determine whether they were MHS or MH normal (MHN) according to the North American Malignant Hyperthermia Group’s test protocol for establishing MH (the in vitro contracture test with halothane and caffeine).During the in vivo challenge, tachycardia, hyperthermia, and hypercapnia developed in 24 dogs, establishing them as MHS. (In contrast to pigs and humans with MH, dogs do not exhibit lactic acidemia, metabolic acidosis, or extensor rigidity.) With the in vitro contracture test, 23 dogs were MHS, 19 were MHN, and 5 were indeterminate. Animals were then tested for linkage to the MHS phenotype. Results of the mutational analysis showed that MH susceptibility in this study colony was transmitted as an autosomal dominant trait. All MHS dogs were heterozygous for the new T1640C mutation found on chromosome 1. None of the MHN dogs carried this mutation. Detection of this mutant allele by clinical challenge and in vitro contracture testing suggests that a dog model may be useful for developing improved phenotypic detection of heterozygotes needed for human diagnosis and genetic investigations.