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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.

Author information

1
Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8556, Japan Department of Neuromuscular Research and Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
2
Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8556, Japan Department of Neuromuscular Research and noguchi@ncnp.go.jp.
3
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Shinjuku, Tokyo 162-8666, Japan.
4
Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8556, Japan Department of Neuromuscular Research and Department of Neurophysiology, Tokyo Medical University, Tokyo 160-8402, Japan.
5
Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8556, Japan.
6
Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan.
7
Department of Pediatrics, Dokkyo Medical University, Koshigaya Hospital, Koshigaya, Saitama 343-8555, Japan.
8
Department of Diabetes and Endocrinology, Osaka Saiseikai Nakatsu Hospital, Osaka 530-0012, Japan.
9
Division of Pediatric Neurology, Kanagawa Children's Medical Center (KCMC), Yokohama 232-8555, Japan.
10
Division of Pediatrics, Yokosuka Kyosai Hospital, Yokosuka, Kanagawa 238-8558, Japan and.
11
Division of Pediatrics, Kawasaki Municipal Hospital, Kawasaki, Kanagawa 210-0013, Japan.
12
Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8556, Japan Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
13
Department of Neuromuscular Research and.
14
Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8556, Japan Department of Neuromuscular Research and.

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.

PMID:
25227914
DOI:
10.1093/hmg/ddu477
[Indexed for MEDLINE]

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