Identical de novo Mutation in the Type 1 Ryanodine Receptor Gene Associated with Fatal, Stress-induced Malignant Hyperthermia in Two Unrelated Families

Abstract

The R3983C mutation potentiates D4505H-mediated sensitization of caffeine-induced RYR1 Ca release when the mutations are in cis (on the same subunit) but not when present on separate subunits. Nevertheless, coexpression of the two variants on separate subunits still resulted in a ∼2-fold increase in caffeine sensitivity, consistent with the observed awake episodes and heat sensitivity.