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对 RYR1 突变 p.Thr84Met 的遗传和功能分析显示其易感性与恶性高热有关。

Genetic and functional analysis of the RYR1 mutation p.Thr84Met revealed a susceptibility to malignant hyperthermia.

机构信息

Department of Anesthesiology and Critical Care, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.

Department of Anesthesiology and Critical Care, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.

出版信息

J Anesth. 2018 Apr;32(2):174-181. doi: 10.1007/s00540-018-2451-6. Epub 2018 Jan 17.

DOI:10.1007/s00540-018-2451-6
PMID:29344738
Abstract

PURPOSE

The aim of this study was to analyze the genetic and functional role of a novel RYR1 variant c.251 C > T (p.Thr84Met) identified in a patient with muscle weakness demonstrating MH susceptibility.

METHODS

DNA testing of family members was conducted for assessment of pathogenicity of the genetic variant. For functional analysis, Ca measurement using patient-derived myotubes and p.Thr84Met RYR1-transfected human embryonic kidney (HEK)-293 cells was performed to evaluate reactivity to RYR1 activators. The half-maximal effective concentration (EC) values of two RYR1 activators, caffeine and 4-chloro-m-cresol (4CmC), were calculated from the acquired dose-response curves. The EC was compared between two groups: for myotubes, the control group and the patient, and for HEK-293 cells, WT and p.Thr84Met.

RESULTS

Dose-response curves for caffeine and 4CmC were shifted to the left in both myotubes and HEK-293 cells compared to controls. The 50% effective concentration values for caffeine and 4CmC were significantly lower in both myotubes and HEK-293 cells compared to controls (P < 0.001 for all comparisons).

CONCLUSIONS

Our results of functional testing indicated RYR1 hypersensitivity to caffeine and 4CmC. We conclude that the genetic variant was associated with MH susceptibility.

摘要

目的

本研究旨在分析在表现出 MH 易感性的肌肉无力患者中发现的新型 RYR1 变异 c.251 C>T（p.Thr84Met）的遗传和功能作用。

方法

对家族成员进行 DNA 测试，以评估遗传变异的致病性。为了进行功能分析，使用患者来源的肌管和 p.Thr84Met RYR1 转染的人胚肾（HEK）-293 细胞进行 Ca 测量，以评估对 RYR1 激活剂的反应性。从获得的剂量-反应曲线计算两种 RYR1 激活剂咖啡因和 4-氯间甲酚（4CmC）的半最大有效浓度（EC）值。将两个 EC 值进行比较：一组是肌管的对照组和患者组，另一组是 HEK-293 细胞的 WT 和 p.Thr84Met 组。

结果

与对照组相比，咖啡因和 4CmC 的剂量-反应曲线在肌管和 HEK-293 细胞中均向左移位。与对照组相比，咖啡因和 4CmC 的 50%有效浓度值在肌管和 HEK-293 细胞中均显著降低（所有比较均 P<0.001）。

结论

我们的功能测试结果表明 RYR1 对咖啡因和 4CmC 敏感。我们得出结论，该遗传变异与 MH 易感性相关。

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