Analysis of point mutations in the ryanodine receptor gene from malignant hyperthermia patients who showed highly accelerated CICR

Malignant hyperthemia （MH）是一个potentially fatal complication of general anesthesia resulting fromabnormal Ca - D12+ c - D1-induced Ca - D12+ c - D1 release (CICR) via the type 1 ryanodine receptor （RYR1）in skeletal muscle. Kawana博士等al. （Department of Pharmacology, Graduate School of Medicine, Department of Pharmacology）The University of Tokyo) had analyzed CICR in biopsied skeletal muscle samples obtained from 84patients who underwent surgery，与标识的三个patients with highly accelerated CICR rates and a clear history of MHincidence. MIH of has a familial backgroundand the presence of mutation in the RYR1 gene has been suspected. We分析genomic DNA preparedfrom the blood samples donated by these patients for determination of the entire 106 exons of theRYR1 gene. We found three point mutations (R4645Q. P4668S，L4838V) with alterations in the coded amino acid within the C-terminal region of the RYR1 gene. Wedid functional assay in CHO cells by expressing rabbit RYR1 channels carrying these mutations.Rabbit RYR1 channels carrying R4645Q and L4838V showed增强灵敏度to caffein. Furthermore，all three MH patients had one of the functionally significant mutations in the RYR1 gene. Weconclude that these point mutations cause malignant hyperthermia to 3 patients with highlyaccerelated cicr。

Malignant hyperthemia (MH) is a potentially fatal complication of general anesthesia resulting from abnormal CaィイD12+ィエD1-induced CaィイD12+ィエD1 release (CICR) via the type 1 ryanodine receptor (RYR1) in skeletal muscle. Dr. Kawana et al. (Department of Pharmacology, Graduate School of Medicine, The University of Tokyo) had analyzed CICR in biopsied skeletal muscle samples obtained from 84 patients who underwent surgery, and identified three patients with highly accelerated CICR rates and a clear history of MH incidence. MIH often has a familial background, and the presence of mutation in the RYR1 gene has been suspected. We analyzed genomic DNA prepared from the blood samples donated by these patients for determination of the entire 106 exons of the RYR1 gene. We found three point mutations (R4645Q. P4668S, L4838V) with alterations in the coded amino acid within the C-terminal region of the RYR1 gene. We did functional assay in CHO cells by expressing rabbit RYR1 channels carrying these mutations. Rabbit RYR1 channels carrying R4645Q and L4838V showed enhanced sensitivity to caffein. Furthermore, all three MH patients had one of the functionally significant mutations in the RYR1 gene. We conclude that these point mutations cause malignant hyperthermia to 3 patients with highly accerelated CICR.