Hum Mol Genet. 2015 Feb 1;24(3):637-48. doi: 10.1093/hmg/ddu477. Epub 2014 Sep 16.
Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca²⁺ channels.
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.
細管集合体ミオパチー(Tubular aggregate myopathy, TAM)は、細管集合体を病理学的特徴とする遺伝性ミオパチーであるが、その遺伝学的背景はこれまでほとんど解明されていなかった。本研究では、常染色体優性遺伝形式を呈するTAM 3家系の遺伝子解析により、ORAI1遺伝子の機能獲得型変異がTAMを引き起こすことをつきとめた。ORAI1変異によりStore-operated Ca2+ entry (SOCE)チャネルが障害され、細胞外から細胞内にカルシウムイオンが過剰に流入することが疾患の原因であることを証明した。