Genetic variation in RYR1 and malignant hyperthermia phenotypes
Genetic variation in RYR1 and malignant hyperthermia phenotypes
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DOI：
10.1093/bja/aep204
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发表时间：
2009-10-01
影响因子：
9.8
通讯作者：
Hopkins, P. M.
中科院分区：
文献类型：
--
作者：
Carpenter, D.;Robinson, R. L.;Hopkins, P. M.
在大多数情况下，恶性高热（MH）与编码骨骼肌兰尼碱受体的基因RYR 1突变有关。我们的主要目的是评估不同的RYR 1变异体是否与MH表型的定量差异相关，使用体外药理学肌肉挛缩反应的程度和基线血清肌酸激酶（CK）浓度来产生一系列MH的定量表型。然后，我们进行了最广泛的RYR 1基因型-表型相关性MH迄今为止，使用504个人从204 MH家庭和23 RYR 1变异。我们还确定了临床表型与实验室表型和RYR 1基因型之间的相关性。我们报告了体外药理学肌肉挛缩反应程度与指标病例临床MH反应开始时间之间的新相关性（P < 0.05）。基线CK浓度与临床发作时间也有显著相关性（P=0.039）。特定的RYR 1变体是每种实验室表型严重程度的重要决定因素（P < 0.0001）。MH表型因不同的RYR 1变体而显着不同。导致更严重的MH表型的变体分布在整个基因中，并且倾向于位于蛋白质中相对保守的位点。RYR 1变异体之间表型严重程度的差异可以解释麻醉期间MH临床发病率的变化，以及为什么某些变异体与运动诱导的横纹肌溶解和中暑有关。它们也可能为特发性高CKa血症的突变筛查策略提供信息。
Malignant hyperthermia (MH) is associated, in the majority of cases, with mutations in RYR1, the gene encoding the skeletal muscle ryanodine receptor. Our primary aim was to assess whether different RYR1 variants are associated with quantitative differences in MH phenotype.The degree of in vitro pharmacological muscle contracture response and the baseline serum creatine kinase (CK) concentration were used to generate a series of quantitative phenotypes for MH. We then undertook the most extensive RYR1 genotype-phenotype correlation in MH to date using 504 individuals from 204 MH families and 23 RYR1 variants. We also determined the association between a clinical phenotype and both the laboratory phenotype and RYR1 genotype.We report a novel correlation between the degree of in vitro pharmacological muscle contracture responses and the onset time of the clinical MH response in index cases (P < 0.05). There was also a significant correlation between baseline CK concentration and clinical onset time (P=0.039). The specific RYR1 variant was a significant determinant of the severity of each laboratory phenotype (P < 0.0001).The MH phenotype differs significantly with different RYR1 variants. Variants leading to more severe MH phenotype are distributed throughout the gene and tend to lie at relatively conserved sites in the protein. Differences in phenotype severity between RYR1 variants may explain the variability in clinical penetrance of MH during anaesthesia and why some variants have been associated with exercise-induced rhabdomyolysis and heat stroke. They may also inform a mutation screening strategy in cases of idiopathic hyperCKaemia.