Novel Mutations in C-terminal Channel Region of the Ryanodine Receptor in Malignant Hyperthermia Patients.

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  • Oyamada Hideto
    Department of Pharmacology, School of Medicine, Showa University
  • Oguchi Keiko
    Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo
  • Saitoh Naoto
    Department of Pharmacology, Graduate School of Medicine, The University of Tokyo
  • Yamazawa Toshiko
    Department of Pharmacology, Graduate School of Medicine, The University of Tokyo
  • Hirose Kenzo
    Department of Pharmacology, Graduate School of Medicine, The University of Tokyo
  • Kawana Yoko
    Department of Pharmacology, Graduate School of Medicine, The University of Tokyo
  • Wakatsuki Kazunao
    Department of Pharmacology, School of Medicine, Showa University
  • Oguchi Katsuji
    Department of Pharmacology, School of Medicine, Showa University
  • Tagami Megumi
    Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo
  • Hanaoka Kazuo
    Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo
  • Endo Makoto
    Saitama Medical School
  • Iino Masamitsu
    Department of Pharmacology, Graduate School of Medicine, The University of Tokyo

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抄録

Malignant hyperthermia (MH) is a pharmacogenetical complication of general anesthesia resulting from abnormal Ca2+-induced Ca2+ release (CICR) via the type 1 ryanodine receptor (RyR1) in skeletal muscles. In this study, we analyzed the genomic DNAs prepared for determination of all the 106 exons of the RyR1 gene from blood samples donated by two MH patients with extremely high CICR rates in their biopsied skeletal muscles and a clear history of MH incidence. Two novel point mutations were found in the exons 96 and 101 with alterations in the coded amino acids within the C-terminal channel region, i.e., Pro4668 to Ser and Leu4838 to Val. The latter mutation was found in both MH patients. Rabbit RyR1 channels carrying corresponding mutations were expressed in CHO cells for functional assay. It was found that the L to V but not the P to S mutation of the RyR1 resulted in enhanced Ca2+ release activity. These results indicate that the L4838V mutation is responsible for the MH incidence. The L4838V mutation is unique because it is the mutation first found within a hydrophobic transmembrane segment of the channel region and should provide further information on the function of the RyR1 as well as for genetic diagnosis of MH.

収録刊行物

  • Jpn.J.Pharmacol.

    Jpn.J.Pharmacol. 88 (2), 159-166, 2002

    公益社団法人 日本薬理学会

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