Which three genetic mutations are associated with malignant hyperthermia?

• A. RYR2; CACNA1D; STAC3
• B. RYR1; CACNA1S; STAC3
• C. RYR1; CACNA1S; RYR3
• D. RYR1; RYR2; CACNA1S

Answer: (B)

Malignant hyperthermia stems from abnormal calcium handling in skeletal muscle when exposed to triggering anesthetics. The primary player is the ryanodine receptor in the sarcoplasmic reticulum, encoded by RYR1; mutations here cause the Ca2+ release channel to overreact, leading to excessive Ca2+ in the muscle cell and a hypermetabolic crisis. The voltage sensor for excitation-contraction coupling, CACNA1S, encodes the Cav1.1 channel; dysfunction here can disrupt the normal signal that prompts Ca2+ release, increasing susceptibility to MH. STAC3 is also involved in the skeletal muscle signaling complex that links depolarization to Ca2+ release, and certain variants have been associated with MH susceptibility. In contrast, RYR2 is the cardiac ryanodine receptor and RYR3 is a different ryanodine receptor subtype not typically linked to skeletal muscle MH, so those genes aren’t part of the usual MH-associated set. Therefore, the best-fitting trio reflects RYR1, CACNA1S, and STAC3 as genes associated with malignant hyperthermia susceptibility.