Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation.

Gilles Morin, Valérie Biancalana, Andoni Echaniz-Laguna, Jean-Baptiste Noury, Xavière Lornage, Maurizio Moggio, Michela Ripolone, Raffaella Violano, Pascale Marcorelles, Denis Maréchal, Florence Renaud, Claude-Alain Maurage, Céline Tard, Jean-Marie Cuisset, Jocelyn Laporte, Johann Böhm

Journal: Human mutation 2021;41(1):17-37

PMID: 31448844

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Abstract

Calcium (Ca ) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca entry, storage, and release. Store-operated Ca entry (SOCE) is a major mechanism controlling extracellular Ca entry, and mainly relies on the accurate interplay between the Ca sensor STIM1 and the Ca channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca homeostasis and are associated with severe human disorders. Recessive loss-of-function mutations impair SOCE and cause combined immunodeficiency, while dominant gain-of-function mutations induce excessive extracellular Ca entry and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). TAM and STRMK are spectra of the same multisystemic disease characterized by muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. To date, 42 TAM/STRMK families have been described, and here we report five additional families for which we provide clinical, histological, ultrastructural, and genetic data. In this study, we list and review all new and previously reported STIM1 and ORAI1 cases, discuss the pathomechanisms of the mutations based on the known functions and the protein structure of STIM1 and ORAI1, draw a genotype/phenotype correlation, and delineate an efficient screening strategy for the molecular diagnosis of TAM/STRMK.

Address: Clinical Genetics, Amiens University Hospital, Amiens, France.; University of Picardy Jules Verne, EA 4666, Amiens, France.; Department of translational medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.; Inserm U1258, Illkirch, France.; CNRS UMR7104, Illkirch, France.; Strasbourg University, Illkirch, France.; Laboratoire Diagnostic Génétique, CHRU, Strasbourg, France.; Department of Neurology, APHP, CHU de Bicêtre, Le Kremlin Bicêtre, France.; French National Reference Center for Rare Neuropathies (NNERF), Le Kremlin Bicêtre, France.; Inserm U1195 & Paris-Sud University, Le Kremlin Bicêtre, France.; Department of Neurology, CHRU Cavale Blanche, Brest, France.; Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.; Department of Pathology - EA 4685 LNB, CHRU Morvan, Brest, France.; Department of Pathology, Lille University Hospital, Lille, France.; CHU Lille, Inserm U1171, Service de neurologie, Centre de Référence des Maladies Neuromusculaires Nord Est Ile-de-France, Lille University, Lille, France.; Service de Neuropédiatrie, CHRU de Lille, Lille, France.

DOI: 10.1002/humu.23899