Research ArticlePhysiology

An RYR1 mutation associated with malignant hyperthermia is also associated with bleeding abnormalities

Sci. Signal.  05 Jul 2016:
Vol. 9, Issue 435, pp. ra68
DOI: 10.1126/scisignal.aad9813

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Sparking greater blood loss

When given certain general anesthetics, individuals with the inherited disorder malignant hyperthermia experience a dangerous increase in body temperature and severe muscle contractions. These life-threatening reactions are caused by excessively high Ca2+ concentrations in skeletal muscle cells resulting from hyperactivity of ryanodine receptor type 1 (RyR1). Lopez et al. investigated the effect of a malignant hyperthermia–associated RYR1 mutation in vascular smooth muscle cells, where local spikes in Ca2+ concentrations (called “Ca2+ sparks”) lead to vasodilation. Some patients with malignant hyperthermia bled for longer than their normal relatives, a phenotype that could result from excessive vasodilation. Consistent with this explanation, mice engineered with a RYR1 mutation found in some patients also bled for longer than their normal counterparts, and Ca2+ sparks were more frequent in vascular smooth muscle cells from mice with the RYR1 mutation. Because RyR1 is also found in other types of smooth muscle tissues, RYR1 mutations could have a wider range of effects than previously suspected. RYR1 mutations could also underlie mild bleeding abnormalities that are common but do not have a clear genetic basis.

Abstract

Malignant hyperthermia is a potentially fatal hypermetabolic disorder triggered by halogenated anesthetics and the myorelaxant succinylcholine in genetically predisposed individuals. About 50% of susceptible individuals carry dominant, gain-of-function mutations in RYR1 [which encodes ryanodine receptor type 1 (RyR1)], though they have normal muscle function and no overt clinical symptoms. RyR1 is predominantly found in skeletal muscle but also at lower amounts in immune and smooth muscle cells, suggesting that RYR1 mutations may have a wider range of effects than previously suspected. Mild bleeding abnormalities have been described in patients with malignant hyperthermia carrying gain-of-function RYR1 mutations. We sought to determine the frequency and molecular basis for this symptom. We found that some patients with specific RYR1 mutations had abnormally high bleeding scores, whereas their healthy relatives did not. Knock-in mice with the malignant hyperthermia susceptibility RYR1 mutation Y522S (MHS RYR1Y522S) had longer bleeding times than their wild-type littermates. Primary vascular smooth muscle cells from RYR1Y522S knock-in mice exhibited a higher frequency of subplasmalemmal Ca2+ sparks, leading to a more negative resting membrane potential. The bleeding defect of RYR1Y522S mice and of one patient was reversed by treatment with the RYR1 antagonist dantrolene, and Ca2+ sparks in primary vascular smooth muscle cells from the MHS RYR1Y522S mice were blocked by ryanodine or dantrolene. Thus, RYR1 mutations may lead to prolonged bleeding by altering vascular smooth muscle cell function. The reversibility of the bleeding phenotype emphasizes the potential therapeutic value of dantrolene in the treatment of such bleeding disorders.

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