title: Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1.
abstract: OBJECTIVE
  To identify the gene mutation of tubular aggregate myopathy (TAM) and gain mechanistic insight into the pathogenesis of the disorder.
  
  
  METHODS
  We described a family affected by autosomal dominant TAM and performed exome and Sanger sequencing to identify mutations. We further analyzed the functional significance of the identified mutation by expression studies and intracellular Ca(2+) measurements.
  
  
  RESULTS
  A 42-year-old man presented with slowly progressive muscle weakness and atrophy in all 4 limbs and the trunk. Muscle biopsy and microscopic examination revealed tubular aggregates in his skeletal muscle. Genetic analysis of this family identified a novel heterozygous mutation, c.1450_1451insGA (p.Ile484ArgfsX21), in stromal interaction molecule 1 (STIM1), a Ca(2+) sensor in sarcoplasmic reticulum. We transfected cultured cells with STIM1 and demonstrated that the mutant STIM1 exhibited aggregation-like appearance in shrunk cytoplasm. Furthermore, we revealed that the intracellular Ca(2+) influx is decreased by the mutant STIM1.
  
  
  CONCLUSIONS
  The novel mutation p.Ile484ArgfsX21 is located in the cytoplasmic C-terminal inhibitory domain (CTID) of STIM1. However, all mutations reported so far in TAM reside in the luminal N-terminal EF hand region. The aggregation-like appearance of STIM1 and the decreased intracellular Ca(2+) influx in cells transfected with CTID mutant are in sharp contrast to these previous reports. Taken together, these findings indicate that mutations of STIM1 cause TAM through the dysregulation of Ca(2+) homeostasis.
authors.affiliation: Department of Neurology (H.O., F.S., Y. Hatanaka, M.I., K.M., M.S.), School of Medicine, and Department of Sport and Medical Science (T.S.), Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Neurology (J.M., J.S., S.T.), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Synthetic Chemistry and Biological Chemistry (Y. Hara), Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Okuma
authors.affiliation: Department of Neurology (H.O., F.S., Y. Hatanaka, M.I., K.M., M.S.), School of Medicine, and Department of Sport and Medical Science (T.S.), Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Neurology (J.M., J.S., S.T.), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Synthetic Chemistry and Biological Chemistry (Y. Hara), Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Saito
authors.affiliation: Department of Neurology (H.O., F.S., Y. Hatanaka, M.I., K.M., M.S.), School of Medicine, and Department of Sport and Medical Science (T.S.), Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Neurology (J.M., J.S., S.T.), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Synthetic Chemistry and Biological Chemistry (Y. Hara), Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.affiliation: Department of Neurology (H.O., F.S., Y. Hatanaka, M.I., K.M., M.S.), School of Medicine, and Department of Sport and Medical Science (T.S.), Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Neurology (J.M., J.S., S.T.), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Synthetic Chemistry and Biological Chemistry (Y. Hara), Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hara
authors.affiliation: Department of Neurology (H.O., F.S., Y. Hatanaka, M.I., K.M., M.S.), School of Medicine, and Department of Sport and Medical Science (T.S.), Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Neurology (J.M., J.S., S.T.), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Synthetic Chemistry and Biological Chemistry (Y. Hara), Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hatanaka
authors.affiliation: Department of Neurology (H.O., F.S., Y. Hatanaka, M.I., K.M., M.S.), School of Medicine, and Department of Sport and Medical Science (T.S.), Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Neurology (J.M., J.S., S.T.), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Synthetic Chemistry and Biological Chemistry (Y. Hara), Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Neurology (H.O., F.S., Y. Hatanaka, M.I., K.M., M.S.), School of Medicine, and Department of Sport and Medical Science (T.S.), Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Neurology (J.M., J.S., S.T.), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Synthetic Chemistry and Biological Chemistry (Y. Hara), Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Neurology (H.O., F.S., Y. Hatanaka, M.I., K.M., M.S.), School of Medicine, and Department of Sport and Medical Science (T.S.), Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Neurology (J.M., J.S., S.T.), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Synthetic Chemistry and Biological Chemistry (Y. Hara), Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Matsumura
authors.affiliation: Department of Neurology (H.O., F.S., Y. Hatanaka, M.I., K.M., M.S.), School of Medicine, and Department of Sport and Medical Science (T.S.), Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Neurology (J.M., J.S., S.T.), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Synthetic Chemistry and Biological Chemistry (Y. Hara), Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Shimizu
authors.affiliation: Department of Neurology (H.O., F.S., Y. Hatanaka, M.I., K.M., M.S.), School of Medicine, and Department of Sport and Medical Science (T.S.), Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Neurology (J.M., J.S., S.T.), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Synthetic Chemistry and Biological Chemistry (Y. Hara), Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Department of Neurology (H.O., F.S., Y. Hatanaka, M.I., K.M., M.S.), School of Medicine, and Department of Sport and Medical Science (T.S.), Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Neurology (J.M., J.S., S.T.), Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and Department of Synthetic Chemistry and Biological Chemistry (Y. Hara), Graduate School of Engineering, Kyoto University, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sonoo