ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:124

Article

McCarl, Christie-Ann^1,2,3  Picard, Capucine^4,7,8  Khalil, Sara¹  Kawasaki, Takumi¹  Roether, Jens^2,3  Papolos, Alexander¹  Kutok, Jeffery⁹  Hivroz, Claire^5,10  LeDeist, Francoise^4,5,11,12  Plogmann, Katrin¹³  Ehl, Stephan¹⁴  Notheis, Gundula¹⁶  Albert, Michael H.¹⁷  Belohradsky, Bernd H.¹⁶  Kirschner, Janbernd¹⁵  Rao, Anjana^2,3  Fischer, Alain^5,6,8  Feske, Stefan^1,2,3 

[1] NYU, Dept Pathol, Langone Med Ctr, New York, NY 10016 USA

[2] Harvard Univ, Sch Med, Dept Pathol, Program Cellular & Mol Med,Childrens Hosp Boston, Boston, MA 02115 USA

[3] Immune Dis Inst, Boston, MA USA

[4] AP HP, Study Ctr Primary Immunodeficiencies, Paris, France

[5] INSERM, U768, Paris, France

[6] Necker Enfants Malades Hosp, Pediat Hematol Immunol Unit, Paris, France

[7] Fac Med Necker Enfants Malad, Human Genet Infect Dis INSERM, U550, Paris, France

[8] Paris Descartes Univ, Paris, France

[9] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[10] Inst Curie, INSERM, U653, Paris, France

[11] Univ Montreal, Dept Microbiol & Immunol, Ctr Hosp Univ St Justine, Montreal, PQ H3C 3J7, Canada

[12] Univ Montreal, Ctr Rech, Ctr Hosp Univ St Justine, Montreal, PQ, Canada

[13] Univ Freiburg, Dept Operat Dent & Periodontol, Freiburg, Germany

[14] Univ Freiburg, Ctr Chron Immunodeficiency, Freiburg, Germany

[15] Univ Freiburg, Dept Neuropediat & Muscle Disorders, Freiburg, Germany

[16] Univ Munich, Dr von Haunersches Kinderspital, Dept Infect & Immun, Munich, Germany

[17] Univ Munich, Dr von Haunersches Kinderspital, Dept Pediat Hematol Oncol, Munich, Germany

关键词: ORAI1;    STIM1;    CRAC;    calcium channel;    Ca2+;    store-operated Ca2+ entry;    T cells;    immunodeficiency;    signal transduction;    congenital myopathy;    anhydrotic ectodermal dysplasia;    dental enamel;    amelogenesis imperfecta;   

DOI  :  10.1016/j.jaci.2009.10.007

来源: Elsevier

【 摘 要 】

Background: Defects in the development or activation of T cells result in immunodeficiency associated with severe infections early in life. T-cell activation requires Ca2+ influx through Ca2+-release activated Ca2+ (CRAC) channels encoded by the gene ORAI1. Objective: Investigation of the genetic causes and the clinical phenotype of immunodeficiency in patients with impaired Ca2+ influx and CRAC channel function. Methods: DNA sequence analysis for mutations in the genes ORAI1, ORAI2, ORAI3, and stromal interaction molecule (STIM) 1 and 2, as well as mRNA and protein expression analysis of ORAI1 in immunodeficient patients. Immunohistochemical analysis of ORAI1 tissue distribution in healthy human donors. Results: We identified mutations in ORAI1 in patients from 2 unrelated families. One patient is homozygous for a frameshift nonsense mutation in ORAI1 (ORAI1-A88SfsX25), and a second patient is compound heterozygous for 2 missense mutations in ORAI1 (ORAI1-A103E/L194P). All 3 mutations abolish ORAI1 expression and impair Ca2+ influx and CRAC channel function. The clinical syndrome associated with ORAI1 deficiency is characterized by immunodeficiency with a defect in the function but not in the development of lymphocytes, congenital myopathy, and anhydrotic ectodermal dysplasia with a defect in dental enamel calcification. In contrast with the limited clinical phenotype, we found ORAI1 protein expression in a wide variety of cell types and organs. Conclusion: Ca2+ influx through ORAI1 is crucial for lymphocyte function in vivo. Despite almost ubiquitous ORAI1 expression, the channel has a nonredundant role in only a few cell types judging from the limited clinical phenotype in ORAI1-deficient patients. (J Allergy Clin Immunol 2009;124:1311-8.)

【 授权许可】

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