RRC ID 67307
Author Endo Y, Noguchi S, Hara Y, Hayashi YK, Motomura K, Miyatake S, Murakami N, Tanaka S, Yamashita S, Kizu R, Bamba M, Goto Y, Matsumoto N, Nonaka I, Nishino I.
Title Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca²⁺ channels.
Journal Hum Mol Genet
Abstract The store-operated Ca(2+) release-activated Ca(2+) (CRAC) channel is activated by diminished luminal Ca(2+) levels in the endoplasmic reticulum and sarcoplasmic reticulum (SR), and constitutes one of the major Ca(2+) entry pathways in various tissues. Tubular aggregates (TAs) are abnormal structures in the skeletal muscle, and although their mechanism of formation has not been clarified, altered Ca(2+) homeostasis related to a disordered SR is suggested to be one of the main contributing factors. TA myopathy is a hereditary muscle disorder that is pathologically characterized by the presence of TAs. Recently, dominant mutations in the STIM1 gene, encoding a Ca(2+) sensor that controls CRAC channels, have been identified to cause tubular aggregate myopathy (TAM). Here, we identified heterozygous missense mutations in the ORAI1 gene, encoding the CRAC channel itself, in three families affected by dominantly inherited TAM with hypocalcemia. Skeletal myotubes from an affected individual and HEK293 cells expressing mutated ORAI1 proteins displayed spontaneous extracellular Ca(2+) entry into cells without diminishment of luminal Ca(2+) or the association with STIM1. Our results indicate that STIM1-independent activation of CRAC channels induced by dominant mutations in ORAI1 cause altered Ca(2+) homeostasis, resulting in TAM with hypocalcemia.
Volume 24(3)
Pages 637-48
Published 2015-2-1
DOI 10.1093/hmg/ddu477
PII ddu477
PMID 25227914
MeSH Adult Calcium / metabolism Calcium Channels / genetics* Calcium Channels / metabolism Child Child, Preschool HEK293 Cells Heterozygote Humans Hypocalcemia / genetics* Male Muscle Fibers, Skeletal / metabolism Muscle Fibers, Skeletal / pathology* Mutation, Missense Myopathies, Structural, Congenital / complications Myopathies, Structural, Congenital / genetics* Myopathies, Structural, Congenital / pathology* ORAI1 Protein Pedigree Stromal Interaction Molecule 1
IF 5.101
Human and Animal Cells 293(RCB1637)