title: Genotype-Phenotype Correlations of Malignant Hyperthermia and Central Core Disease Mutations in the Central Region of the RYR1 Channel.
abstract: Type 1 ryanodine receptor (RYR1) is a Ca2+release channel in the sarcoplasmic reticulum of skeletal muscle and is mutated in some muscle diseases, including malignant hyperthermia (MH) and central core disease (CCD). Over 200 mutations associated with these diseases have been identified, and most mutations accelerate Ca2+-induced Ca2+release (CICR), resulting in abnormal Ca2+homeostasis in skeletal muscle. However, it remains largely unknown how specific mutations cause different phenotypes. In this study, we investigated the CICR activity of 14 mutations at 10 different positions in the central region of RYR1 (10 MH and four MH/CCD mutations) using a heterologous expression system in HEK293 cells. In live-cell Ca2+imaging, the mutant channels exhibited an enhanced sensitivity to caffeine, a reduced endoplasmic reticulum Ca2+content, and an increased resting cytoplasmic Ca2+level. The three parameters for CICR (Ca2+sensitivity for activation, Ca2+sensitivity for inactivation, and attainable maximum activity, i.e., gain) were obtained by [3H]ryanodine binding and fitting analysis. The mutant channels showed increased gain and Ca2+sensitivity for activation in a site-specific manner. Genotype-phenotype correlations were explained well by the near-atomic structure of RYR1. Our data suggest that divergent CICR activity may cause various disease phenotypes by specific mutations.
authors: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan. takashim@juntendo.ac.jp.
authors: Takashi
authors: T
authors: Murayama
authors: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors: Nagomi
authors: N
authors: Kurebayashi
authors: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors: Haruo
authors: H
authors: Ogawa
authors: Department of Molecular Physiology, Jikei University School of Medicine, Tokyo, Japan.
authors: Toshiko
authors: T
authors: Yamazawa
authors: Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan.
authors: Hideto
authors: H
authors: Oyamada
authors: Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Junji
authors: J
authors: Suzuki
authors: Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Kazunori
authors: K
authors: Kanemaru
authors: Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan.
authors: Katsuji
authors: K
authors: Oguchi
authors: Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors: Masamitsu
authors: M
authors: Iino
authors: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors: Takashi
authors: T
authors: Sakurai
mesh_terms: D002118:Calcium / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D020512:Myopathy, Central Core / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium
keywords: calcium release channel; calcium-induced calcium release; central core disease; genotype-phenotype correlation; malignant hyperthermia; muscle disease; ryanodine receptor; sarcoplasmic reticulum; skeletal muscle