Identification and functional characterization of a novel ryanodine receptor mutation causing malignant hyperthermia in North American and South American families

Malignant hyperthermia is a pharmacogenetic disorder associated with mutati ons in Ca2+ regulatory proteins. It manifests as a hypermetabolic crisis tr iggered by commonly used anesthetics. Malignant hyperthermia susceptibility is a dominantly inherited predisposition to malignant hyperthermia that ca n be diagnosed by using caffeine/halothane contracture tests. In a multigen erational North American family with a severe form of malignant hyperthermi a that has caused four deaths, a novel RYR1 A2350T missense mutation was id entified in all individuals testing positive for malignant hyperthermia sus ceptibility. The same A2350T mutation was identified in an Argentinean fami ly with two known fatal MH reactions. Functional analysis in HEK-293 cells revealed an altered Ca2+ dependence and increased caffeine sensitivity of t he expressed mutant protein thus confirming the pathogenic potential of the RYR1 A2350T mutation. (C) 2001 Elsevier Science B.V. All rights reserved.