The genetic basis of malignant hyperthermia.
Anaesthesia can induce skeletal muscle rigidity, hypermetabolism and high fever in humans genetically predisposed to malignant hyperthermia. If not immediately reversed, such episodes can lead to tissue damage and death. In swine with the corresponding condition, stress can induce death or lead to devalued meat products. Since muscle contraction is controlled by sarcoplasmic Ca2+, the abnormality, as reviewed here by David H. MacLennan, could reside in the skeletal muscle Ca(2+)-release channel gene, RYR1. Several observations support the view that a single RYR1 mutation is causal of malignant hyperthermia in all breeds of pigs and in at least some human families: the substitution of Cys for Arg615 as the sole deduced amino acid sequence change in a comparison of malignant hyperthermia and normal porcine RYR1 cDNAs; the linkage of this mutation to malignant hyperthermia in over 450 pigs in six breeds, including 338 meioses; and the appearance of the corresponding mutation, Cys for Arg614, across a species barrier, in a few human families, where it also cosegregates with malignant hyperthermia. Linkage of malignant hyperthermia to RYR1 is, however, not observed in all human families with malignant hyperthermia. Accordingly, other abnormal genes that may cause the condition are being sought.
MacLennan
D H
DH
Banting and Best Department of Medical Research, University of Toronto, Ontario, Canada.
D000758:Anesthesia; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000378:metabolism / Q000662:veterinary; D009119:Muscle Contraction; D009154:Mutation; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013552:Swine; D013553:Swine Diseases / Q000235:genetics* / Q000378:metabolism
D015220:Calcium Channels; D011950:Receptors, Cholinergic; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium