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Association of a mutation in the ryanodine receptor 1 gene with equine malignant hyperthermia
Author(s) -
Aleman Monica,
Riehl Joyce,
Aldridge Brian M.,
Lecouteur Richard A.,
Stott Jeffrey L.,
Pessah Isaac N.
Publication year - 2004
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.20084
Subject(s) - malignant hyperthermia , ryanodine receptor , mutation , genetics , gene , cancer research , biology , medicine , receptor , pathology
Equine malignant hyperthermia (MH) has been suspected but never genetically confirmed. In this study, we investigated whether mutations in a candidate gene, RyR1 , were associated with MH in two clinically affected horses. RyR1 gene sequences revealed polymorphisms in exons 15, 17, and 46 in WT RyR1 and MH RyR1 horses with one derived amino acid change in MH RyR1 exon 46, R2454G. The MH RyR1 horses were genetically heterozygous for this mutation, but presented an MH phenotype with halothane challenge. Skeletal sarcoplasmic reticulum from a R2454G heterozygote collected during a fulminant MH episode showed significantly higher affinity and density of [ 3 H]ryanodine‐binding sites compared to WT RyR1, but no differences in Ca 2+ , Mg 2+ , and caffeine modulation. In conclusion, an autosomal missense mutation in RyR1 is associated with MH in the horse, providing a screening test for susceptible individuals. [ 3 H]ryanodine‐binding analysis suggests that long‐lasting changes in RyR1 conformation persists in vitro after the triggering event. Muscle Nerve 30: 356–365, 2004