Out-licensing

Mouse Model of Malignant Hyperthermia and Associated Myopathy (RyR1 Y522S)

Introduction/Background

Malignant hyperthermia (MH) is a life-threatening disorder characterized by skeletal muscle rigidity and elevated body temperature in response to halogenated anaesthetics such as isoflurane or halothane. Mutation of tyrosine 522 of RyR1 (the predominant skeletal muscle calcium release channel) to serine has been associated with human malignant hyperthermia.

Aims/Hypothesis

The developers created mice harbouring this mutation, and they represent the first murine model of human malignant hyperthermia.

Research

Mice homozygous for the Y522S mutation exhibit skeletal defects and die during embryonic development or soon after birth. Heterozygous mice, which correspond to the human occurrence of this mutation, are MH susceptible, experiencing whole body contractions and elevated core temperatures in response to isoflurane exposure or heat stress. Skeletal muscles from heterozygous mice exhibit increased susceptibility to caffeine- and heat-induced contractures in vitro. In addition, the heterozygous expression of the mutation results in enhanced RyR1 sensitivity to activation by temperature, caffeine and voltage but not uncompensated sarcoplasmic reticulum calcium leak or store depletion.

Conclusion

The developers show that the heterozygous expression of the Y522S mutation confers susceptibility to both heat- and anaesthetic-induced MH responses. The mice contain Cre-lox technology.

The developers show that the Y522S mutation in RyR1 causes Ca2+ leak which drives increased generation of reactive nitrogen species which increases the temperature sensitivity of RyR1 activation and underlies heat stroke and sudden death.

Relevance/Opportunity

Mice will be distributed by Baylor's Center for Comparative Medicine. The mice are available either in the C57B6 background or the CD1 background. Available for non-exclusive license. Please enquire quoting reference no. 06-073.

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