title: 50 years to diagnosis: Autosomal dominant tubular aggregate myopathy caused by a novel STIM1 mutation.
abstract: Tubular aggregates in human muscle biopsies have been reported to occur in a variety of acquired and hereditary neuromuscular conditions since 1964. Recently mutations in the gene encoding the main calcium sensor in the sarcoplasmic reticulum, stromal interaction molecule 1 (STIM1), have been identified as a cause of autosomal dominant tubular aggregate myopathy. We studied a German family with tubular aggregate myopathy and defined cellular consequences of altered STIM1 function. Both patients in our family had early progressive myopathy with proximal paresis of arm and leg muscles, scapular winging, ventilatory failure, joint contractures and external ophthalmoplegia. One patient had a well-documented disease course over 50 years. Sequencing of the STIM1 gene revealed a previously unreported missense mutation (c.242G>A; p.Gly81Asp) located in the first calcium binding EF domain. Functional characterization of the new STIM1 mutation by calcium imaging revealed that calcium influx was significantly increased in primary myoblasts of the index patient compared to controls pointing at a severe alteration of intracellular calcium homeostasis. This new family widens the spectrum of STIM1-associated myopathies to a more severe phenotype.
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany. Electronic address: maggie.walter@lrz.uni-muenchen.de.
authors.forename: Maggie C
authors.initials: MC
authors.lastname: Walter
authors.affiliation: Institute of Pathophysiology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rossius
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zitzelsberger
authors.affiliation: Department of Neurology, Ruhr-University of Bochum, Bochum, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Vorgerd
authors.affiliation: Department of Neuropaediatrics, Dr.-von-Hauner'sches Kinderspital, University of Munich, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Müller-Felber
authors.affiliation: Department of Radiology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Ertl-Wagner
authors.affiliation: Institute of Pathophysiology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Pathophysiology, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Brinkmeier
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
mesh_terms: D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018450:Disease Progression; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000648:ultrastructure; D020125:Mutation, Missense; D032446:Myoblasts / Q000378:metabolism; D020914:Myopathies, Structural, Congenital / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D000071737:Stromal Interaction Molecule 1; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: Calcium imaging; Myopathy; STIM1; Tubular aggregates