title: Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca²⁺ channels.
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.
authors.affiliation: 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.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Endo
authors.affiliation: 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.
authors.forename: Satoru
authors.initials: S
authors.lastname: Noguchi
authors.affiliation: 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.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hara
authors.affiliation: 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.
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.affiliation: Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8556, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Motomura
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Department of Pediatrics, Dokkyo Medical University, Koshigaya Hospital, Koshigaya, Saitama 343-8555, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Murakami
authors.affiliation: Department of Diabetes and Endocrinology, Osaka Saiseikai Nakatsu Hospital, Osaka 530-0012, Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Division of Pediatric Neurology, Kanagawa Children's Medical Center (KCMC), Yokohama 232-8555, Japan.
authors.forename: Sumimasa
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Division of Pediatrics, Yokosuka Kyosai Hospital, Yokosuka, Kanagawa 238-8558, Japan and.
authors.forename: Rika
authors.initials: R
authors.lastname: Kizu
authors.affiliation: Division of Pediatrics, Kawasaki Municipal Hospital, Kawasaki, Kanagawa 210-0013, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Bamba
authors.affiliation: 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.
authors.forename: Yu-Ichi
authors.initials: Y
authors.lastname: Goto
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Neuromuscular Research and.
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.affiliation: Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8556, Japan Department of Neuromuscular Research and.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
mesh_terms: D000328:Adult; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D006996:Hypocalcemia / Q000235:genetics*; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology*; D020125:Mutation, Missense; D020914:Myopathies, Structural, Congenital / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D000071740:ORAI1 Protein; D010375:Pedigree; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D002118:Calcium