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Genotype–Phenotype Correlations of Malignant Hyperthermia and Central Core Disease Mutations in the Central Region of the RYR1 Channel
Author(s) -
Murayama Takashi,
Kurebayashi Nagomi,
Ogawa Haruo,
Yamazawa Toshiko,
Oyamada Hideto,
Suzuki Junji,
Kanemaru Kazunori,
Oguchi Katsuji,
Iino Masamitsu,
Sakurai Takashi
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23072
Subject(s) - ryr1 , malignant hyperthermia , ryanodine receptor , central core disease , biology , endoplasmic reticulum , skeletal muscle , mutant , phenotype , mutation , microbiology and biotechnology , genetics , endocrinology , pathology , gene , medicine
Type 1 ryanodine receptor (RYR1) is a Ca 2+ 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 Ca 2+ ‐induced Ca 2+ release (CICR), resulting in abnormal Ca 2+ 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 Ca 2+ imaging, the mutant channels exhibited an enhanced sensitivity to caffeine, a reduced endoplasmic reticulum Ca 2+ content, and an increased resting cytoplasmic Ca 2+ level. The three parameters for CICR (Ca 2+ sensitivity for activation, Ca 2+ sensitivity for inactivation, and attainable maximum activity, i.e., gain) were obtained by [ 3 H]ryanodine binding and fitting analysis. The mutant channels showed increased gain and Ca 2+ 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.