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ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy.
Hum Mutat. 2017 04; 38(4):426-438.HM

Abstract

Calcium (Ca2+) is a physiological key factor, and the precise modulation of free cytosolic Ca2+ levels regulates multiple cellular functions. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling Ca2+ homeostasis, and is mediated by the concerted activity of the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, whereas recessive loss-of-function mutations are associated with immunodeficiency. Here, we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI1 channels, whereas T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation-dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non-muscle features of our patients strongly suggests that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca2+ homeostasis and leading to muscle dysfunction.

Authors+Show Affiliations

Departement of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France. Inserm, U964, Illkirch, France. CNRS, UMR7104, Illkirch, France. Fédération de Médecine Translationnelle, University of Strasbourg, Illkirch, France. Collège de France, Chaire de Génétique Humaine, Illkirch, France.Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK. Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. Institut de Myologie, GHU La Pitie-Salpetriere, Paris, France.Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK. Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.Departement of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France. Inserm, U964, Illkirch, France. CNRS, UMR7104, Illkirch, France. Fédération de Médecine Translationnelle, University of Strasbourg, Illkirch, France. Collège de France, Chaire de Génétique Humaine, Illkirch, France.Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.Department of Pathology, Royal Preston Hospital, Preston, UK.Department of Paediatric Neurology, Royal Preston Hospital, Preston, UK.Department of Neurology, Royal Preston Hospital, Preston, UK.Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. Institut de Myologie, GHU La Pitie-Salpetriere, Paris, France.Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK. Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.Departement of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France. Inserm, U964, Illkirch, France. CNRS, UMR7104, Illkirch, France. Fédération de Médecine Translationnelle, University of Strasbourg, Illkirch, France. Collège de France, Chaire de Génétique Humaine, Illkirch, France.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28058752

Citation

Böhm, Johann, et al. "ORAI1 Mutations With Distinct Channel Gating Defects in Tubular Aggregate Myopathy." Human Mutation, vol. 38, no. 4, 2017, pp. 426-438.
Böhm J, Bulla M, Urquhart JE, et al. ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy. Hum Mutat. 2017;38(4):426-438.
Böhm, J., Bulla, M., Urquhart, J. E., Malfatti, E., Williams, S. G., O'Sullivan, J., Szlauer, A., Koch, C., Baranello, G., Mora, M., Ripolone, M., Violano, R., Moggio, M., Kingston, H., Dawson, T., DeGoede, C. G., Nixon, J., Boland, A., Deleuze, J. F., ... Laporte, J. (2017). ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy. Human Mutation, 38(4), 426-438. https://doi.org/10.1002/humu.23172
Böhm J, et al. ORAI1 Mutations With Distinct Channel Gating Defects in Tubular Aggregate Myopathy. Hum Mutat. 2017;38(4):426-438. PubMed PMID: 28058752.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy. AU - Böhm,Johann, AU - Bulla,Monica, AU - Urquhart,Jill E, AU - Malfatti,Edoardo, AU - Williams,Simon G, AU - O'Sullivan,James, AU - Szlauer,Anastazja, AU - Koch,Catherine, AU - Baranello,Giovanni, AU - Mora,Marina, AU - Ripolone,Michela, AU - Violano,Raffaella, AU - Moggio,Maurizio, AU - Kingston,Helen, AU - Dawson,Timothy, AU - DeGoede,Christian G, AU - Nixon,John, AU - Boland,Anne, AU - Deleuze,Jean-François, AU - Romero,Norma, AU - Newman,William G, AU - Demaurex,Nicolas, AU - Laporte,Jocelyn, Y1 - 2017/02/02/ PY - 2016/07/18/received PY - 2017/01/02/accepted PY - 2017/1/7/pubmed PY - 2018/1/10/medline PY - 2017/1/7/entrez KW - ORAI1 KW - SOCE KW - STIM1 KW - Stormorken syndrome KW - calcium KW - tubular aggregate myopathy SP - 426 EP - 438 JF - Human mutation JO - Hum. Mutat. VL - 38 IS - 4 N2 - Calcium (Ca2+) is a physiological key factor, and the precise modulation of free cytosolic Ca2+ levels regulates multiple cellular functions. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling Ca2+ homeostasis, and is mediated by the concerted activity of the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, whereas recessive loss-of-function mutations are associated with immunodeficiency. Here, we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI1 channels, whereas T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation-dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non-muscle features of our patients strongly suggests that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca2+ homeostasis and leading to muscle dysfunction. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/28058752/ORAI1_Mutations_with_Distinct_Channel_Gating_Defects_in_Tubular_Aggregate_Myopathy_ L2 - https://doi.org/10.1002/humu.23172 DB - PRIME DP - Unbound Medicine ER -