Assessing the pathogenicity of RYR1 variants in malignant hyperthermia

被引:14
|
作者
Merritt, A. [1 ]
Booms, P. [1 ]
Shaw, M-A. [1 ]
Miller, D. M. [1 ,2 ]
Daly, C. [2 ]
Bilmen, J. G. [1 ,2 ]
Stowell, K. M. [3 ]
Allen, P. D. [4 ]
Steele, D. S. [5 ]
Hopkins, P. M. [1 ,2 ]
机构
[1] Univ Leeds, Leeds Inst Biomed & Clin Sci, Leeds, W Yorkshire, England
[2] St James Univ Hosp, Malignant Hyperthermia Unit, Leeds, W Yorkshire, England
[3] Massey Univ, Inst Fundamental Sci, Palmerston North, New Zealand
[4] Univ Calif Davis, Dept Mol Biosci, Davis, CA USA
[5] Univ Leeds, Sch Biomed Sci, Leeds, W Yorkshire, England
基金
美国国家卫生研究院;
关键词
malignant hyperthermia; genetics; diagnosis; physiopathology; HEK293; cells; calcium signaling; RYR1; CENTRAL CORE DISEASE; MUSCLE RYANODINE RECEPTOR; CA2+ RELEASE; FUNCTIONAL-CHARACTERIZATION; MUTATIONS; SUSCEPTIBILITY; CHANNEL; SENSITIVITY; CELLS; EXPRESSION;
D O I
10.1093/bja/aex042
中图分类号
R614 [麻醉学];
学科分类号
100217 ;
摘要
Background. Missense variants in the ryanodine receptor 1 gene (RYR1) are associated with malignant hyperthermia but only a minority of these have met the criteria for use in predictive DNA diagnosis. We examined the utility of a simplified method of segregation analysis and a functional assay for determining the pathogenicity of recurrent RYR1 variants associated with malignant hyperthermia. Methods. We identified previously uncharacterised RYR1 variants found in four or more malignant hyperthermia families and conducted simplified segregation analyses. An efficient cloning and mutagenesis strategy was used to express ryanodine receptor protein containing one of six RYR1 variants in HEK293 cells. Caffeine-induced calcium release, measured using a fluorescent calcium indicator, was compared in cells expressing each variant to that in cells expressing wild type ryanodine receptor protein. Results. We identified 43 malignant hyperthermia families carrying one of the six RYR1 variants. There was segregation of genotype with the malignant hyperthermia susceptibility phenotype in families carrying the p.E3104K and p.D3986E variants, but the number of informative meioses limited the statistical significance of the associations. HEK293 functional assays demonstrated an increased sensitivity of RyR1 channels containing the p.R2336H, p.R2355W, p.E3104K, p.G3990V and p.V4849I compared with wild type, but cells expressing p.D3986E had a similar caffeine sensitivity to cells expressing wild type RyR1. Conclusions. Segregation analysis is of limited value in assessing pathogenicity of RYR1 variants in malignant hyperthermia. Functional analyses in HEK293 cells provided evidence to support the use of p.R2336H, p.R2355W, p.E3104K, p.G3990V and p.V4849I for diagnostic purposes but not p.D3986E.
引用
收藏
页码:533 / 543
页数:11
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