Functional analysis of RYR1 variants linked to malignant hyperthermia

J. Stephens, A. Schiemann, C. Roesl, Dorota M. Miller, S. Massey, N. Pollock, T. Bulger, K. Stowell
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引用次数: 14

Abstract

ABSTRACT Malignant hyperthermia manifests as a rapid and sustained rise in temperature in response to pharmacological triggering agents, e.g. inhalational anesthetics and the muscle relaxant suxamethonium. Other clinical signs include an increase in end-tidal CO2, increased O2 consumption, as well as tachycardia, and if untreated a malignant hyperthermia episode can result in death. The metabolic changes are caused by dysregulation of skeletal muscle Ca2+ homeostasis, resulting from a defective ryanodine receptor Ca2+ channel, which resides in the sarcoplasmic reticulum and controls the flux of Ca2+ ions from intracellular stores to the cytoplasm. Most genetic variants associated with susceptibility to malignant hyperthermia occur in the RYR1 gene encoding the ryanodine receptor type 1. While malignant hyperthermia susceptibility can be diagnosed by in vitro contracture testing of skeletal muscle biopsy tissue, it is advantageous to use DNA testing. Currently only 35 of over 400 potential variants in RYR1 have been classed as functionally causative of malignant hyperthermia and thus can be used for DNA diagnostic tests. Here we describe functional analysis of 2 RYR1 variants (c. 7042_7044delCAG, p.ΔGlu2348 and c.641C>T, p.Thr214Met) that occur in the same malignant hyperthermia susceptible family. The p.Glu2348 deletion, causes hypersensitivity to ryanodine receptor agonists using in vitro analysis of cloned human RYR1 cDNA expressed in HEK293T cells, while the Thr214Met substitution, does not appear to significantly alter sensitivity to agonist in the same system. We suggest that the c. 7042_7044delCAG, p.ΔGlu2348 RYR1 variant could be added to the list of diagnostic mutations for susceptibility to malignant hyperthermia.
与恶性高热相关的RYR1变异的功能分析
恶性高热表现为对药理学触发剂(如吸入麻醉剂和肌肉松弛剂磺胺松)的反应,体温迅速持续升高。其他临床症状包括潮末CO2升高、耗氧量增加以及心动过速,如果不治疗,恶性高热发作可导致死亡。代谢变化是由骨骼肌Ca2+稳态失调引起的,这是由位于肌浆网的ryanodine受体Ca2+通道缺陷引起的,该通道控制Ca2+离子从细胞内储存到细胞质的通量。大多数与恶性高热易感性相关的遗传变异发生在编码ryanodine受体1型的RYR1基因中。虽然恶性高热易感性可以通过骨骼肌活检组织的体外挛缩测试来诊断,但使用DNA测试是有利的。目前,在RYR1的400多种潜在变异中,只有35种被归类为恶性高热的功能性病因,因此可用于DNA诊断测试。在这里,我们描述了2个RYR1变异(c. 7042_7044delCAG, p.ΔGlu2348和c. 641c >T, p.Thr214Met)在同一恶性高热易感家族中的功能分析。通过对HEK293T细胞中表达的克隆人RYR1 cDNA的体外分析,p.Glu2348缺失会导致对ryanodine受体激动剂的超敏反应,而Thr214Met替换似乎不会显著改变同一系统中对激动剂的敏感性。我们建议将c. 7042_7044delCAG, p.ΔGlu2348 RYR1变异添加到恶性高热易感性的诊断突变列表中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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