title: Novel mutations in C-terminal channel region of the ryanodine receptor in malignant hyperthermia patients.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Oyamada
authors.forename: Keiko
authors.initials: K
authors.lastname: Oguchi
authors.forename: Naoto
authors.initials: N
authors.lastname: Saitoh
authors.forename: Toshiko
authors.initials: T
authors.lastname: Yamazawa
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hirose
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kawana
authors.forename: Kazunao
authors.initials: K
authors.lastname: Wakatsuki
authors.forename: Katsuji
authors.initials: K
authors.lastname: Oguchi
authors.forename: Megumi
authors.initials: M
authors.lastname: Tagami
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hanaoka
authors.forename: Makoto
authors.initials: M
authors.lastname: Endo
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Iino
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008305:Malignant Hyperthermia / Q000097:blood / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D011247:Pregnancy; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D004247:DNA; D002118:Calcium