PHENOTYPES ASSOCIATED WITH MALIGNANT HYPERTHERMIA SUSCEPTIBILITY IN SWINE GENOTYPED AS HOMOZYGOUS OR HETEROZYGOUS FOR THE RYANODINE RECEPTOR MUTATION

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Abstract
We have examined the phenotypic expression of several parameters associated with malignant hyperthermia (MH) susceptibility in three groups (homozygous normal, homozygous abnormal and heterozygous) of Yorkshire/Duroc swine genotyped by a mutation in the ryanodine receptor. Subgroups of homozygous abnormals were classified further by the appearance or absence of muscle rigidity on prolonged in vivo challenge with halothane and suxamethonium. Four swine heterozygous for the proposed MH mutation were indistinguishable from five homozygous normal swine in temperature, heart rate, lactate concentrations, base excess and pH determined during the prolonged halothane and suxamethonium challenge. Resting creatine kinase concentrations, the in vivo barnyard challenge, the in vitro contracture response of skeletal muscle to 3% halothane and the threshold for Ca2+-induced Ca2+ release were also similar for subgroups of homozygous normals and heterozygotes. Therefore, inheritance of only one allele carrying the defect in the ryano dine receptor does not significantly alter phenotypes associated with MH susceptibility in this strain of swine. As four swine homozygous for the proposed MH defect did not exhibit rigidity and three of these had no other signs of MH on prolonged halothane and suxamethonium challenge, we conclude that the reported mutation in the ryanodine receptor may be necessary, but is not sufficient, for consistently eliciting the malignant hyperthermia syndrome. These findings suggest that a modulator of the syndrome may explain variability within indiv iduals in human MH.

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