| Project/Area Number |
10671405
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Anesthesiology/Resuscitation studies
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| Research Institution | The University of Tokyo |
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Principal Investigator |
HAGRWARA Keiko Oguchi Branch Hospital of University of Tokyo Department of Anesthesiology Assistant Professor, 医学部・付属病院・分院, 教務職員 (80292879)
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| Co-Investigator(Kenkyū-buntansha) |
IINO Masamitsu University of Tokyo Department of Pharmacology Graduate School of Medicine Professor, 医学部, 教授 (50133939)
TAGAMI Megumi Branch Hospital of University of Tokyo Department of Anesthesiology Associate Professor, 医学部・付属病院・分院, 助教授 (90107657)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1998: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | Malignant Hyperthermia / CICR / RYR1 / point mutations / リアノジン受容体遺伝子(RYR1) / リアノジン受容体遺伝子(RYRI) |
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| Research Abstract |
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.
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