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

Malignant hyperthemia （MH） is a potentially fatal complication of general anesthesia resulting from abnormal Ca D12+ y D1-induced Ca D12 + y D1 release （CICR） via the type 1 ryanodine receptor （RYR1） in skeletal muscle。Dr. Kawana等人（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 h\of MH incidence。MIH·福特有一个家庭的背景，而且RYR 1基因的突变的存在被怀疑。我们分析了从这些患者中捐赠的血液样本中提取的基因组DNA，以确定RYR 1基因的106个区域。We found three point mutations （R4645Q。P4668 S、L4838 V） with alterations in the coded amino acid within the C-terminal region of the RYR1gene。We did functional assay in CHO cells by expressing rabbit RYR1 channels carrying these mutations。Rabbit RYR1 channels carrying R4645Q and L4838V showed enh？sensitivity to caffein。Furthermore，所有三位MH患者都有RYR 1基因中的功能上有意义的突变。我们将这些点的突变归因于恶性超热，导致3个具有高度敏感性的CICR的患者。

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.