Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis

摘要: The skeletal muscle ryanodine receptor gene (RYR1; OMIM 180901) on chromosome 19q13.1 encodes the calcium release channel. To date, more than 25 missense mutations have been identified in RYR1 and are associated with central core disease (CCD; 117000) and/or malignant hyperthermia susceptibility phenotype (MHS1; 145600). majority of clustered N-terminal hydrophilic domain protein. Only four so far highly conserved C-terminal region encoding luminal/transmembrane protein which forms ion pore. Three these found to segregate pure or mixed CCD. We screened for 50 European patients, diagnosed clinically histologically as having five (four them novel) 13 index patients. cluster exons 101 102 replace amino acids all known vertebrate RYR genes. In order study functional effect mutations, we immortalized B-lymphocytes from some patients studied their [Ca2+] i homeostasis. show that lymphoblasts carrying newly exhibit: (i) a intracellular stores absence any pharmacological activators RYR; (ii) significantly smaller thapsigargin-sensitive stores, compared control individuals; (iii) normal sensitivity inhibitor dantrolene. Our data suggest hot spot leading CCD phenotype. If alterations mutated channels observed lymphoblastoid cells also present muscles this could explain predominant symptom CCD, i.e. chronic weakness. Finally, homeostasis naturally expressing offers novel non-invasive approach gain insights into pathogenesis MH