Mutation in a Skeletal Muscle Calcium Channel Confers Susceptibility to Heat and Anesthetic-Induced Malignant Hyperthermia

Isaac N. Pessah, Ph.D.
University of California Davis
P01ES11269

Background: Malignant Hyperthermia (MH) is a life-threatening inherited muscle condition in which sustained contractions of muscles may occur in response to specific drugs such as the anesthetics halothane, isoflurane, enflurane, etc. and certain muscle relaxants. The exact number of MH susceptible individuals is unknown, but experts believe that it is a rare condition with less than 1 person in 10,000 being affected. A mutation which causes a substitution of tyrosine to serine at amino acid residue 522 of a skeletal muscle calcium release channel protein has been associated with human MH. Many people with MH susceptibility are unaware of their condition, and more than 50% of MH susceptible individuals may have successful anesthesia before they learn that they are susceptible. Often, it is only when a severe or fatal reaction to anesthesia occurs that a diagnosis is made.

The term "malignant" in malignant hyperthermia has nothing to do with cancer. It refers to the alarming death rate that occurred twenty or more years ago. Then fatalities from MH reactions approached 90%. Today, in developing countries, mortality remains at about 50%. In developed countries, however, mortality is now less than 10% due primarily to the availability of an effective antidote (dantrolene), to increased awareness of MH within the medical community, and to vigilant care and use of modern monitors during anesthesia.

Advance: NIEHS-supported researchers have developed a transgenic mouse model of human MH containing the same mutation. They found that mice homozygous for the mutation exhibited skeletal defects and died during development or soon after birth. Mice heterozygous for the mutation, which corresponds to the condition in humans, experienced whole-body skeletal muscle contractions and elevated body temperatures upon exposure to isoflurane or heat stress. Also, heterozygous expression of the mutation results in increased sensitivity of the calcium channel to activation by temperature, caffeine, and voltage.

Implications: This new mouse model of the human condition of MH will continue to provide insight into the condition. Having a research tool to study the condition in controlled laboratory experiments will be essential in developing new treatments or screening tools for people susceptible for MH.

Citation: Chelu MG, Goonasekera SA, Durham WJ, Tang W, Lueck JD, Riehl J, Pessah IN, Zhang P, Bhattacharjee MB, Dirksen RT, Hamilton SL. Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB J. 2006 Feb;20(2):329-30.