ORAI1 mutations abolishing store-operated Ca²⁺ entry cause anhidrotic ectodermal dysplasia with immunodeficiency - 05/10/18

Doi : 10.1016/j.jaci.2017.10.031

Jayson Lian, BA ^a,^{∗
These authors contributed equally to this work.}, Mario Cuk, MD, PhD ^b,^{∗
These authors contributed equally to this work.}, Sascha Kahlfuss, MD ^a,^{∗
These authors contributed equally to this work.}, Lina Kozhaya, MA ^c, Martin Vaeth, PhD ^a, Frédéric Rieux-Laucat, PhD ^d,^e, Capucine Picard, MD, PhD ^e,^f, Melina J. Benson, MD ^a, Antonia Jakovcevic, MD ^g, Karmen Bilic, MD ^h, Iva Martinac, MD ^b, Peter Stathopulos, PhD ⁱ, Imre Kacskovics, DVM, PhD ^j, Thomas Vraetz, MD ^k, Carsten Speckmann, MD ^k,^l, Stephan Ehl, MD ^k,^l, Thomas Issekutz, MD ^m, Derya Unutmaz, MD ^c, Stefan Feske, MD ^a,^⁎
^a Department of Pathology, New York University School of Medicine, New York, NY
^b Department of Pediatrics, University Hospital Centre Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia
^c Jackson Laboratory for Genomic Medicine, Farmington, Conn
^d INSERM UMR 1163, Laboratory of the Immunogenetics of Pediatric Autoimmune Diseases, Paris, France
^e INSERM UMR1163, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France
^f Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), Necker Medical School, Paris, France
^g Department of Pathology and Cytology, University Hospital Centre Zagreb, Zagreb, Croatia
^h Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia
ⁱ Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
^j ImmunoGenes, Budapest, Hungary
^k Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^l Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^m Division of Immunology, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada

^∗Corresponding author: Stefan Feske, MD, Department of Pathology, New York University School of Medicine, New York, NY 10016.Department of PathologyNew York University School of MedicineNew YorkNY10016

Abstract

Background

Store-operated Ca²⁺ entry (SOCE) through Ca²⁺ release–activated Ca²⁺ channels is an essential signaling pathway in many cell types. Ca²⁺ release–activated Ca²⁺ channels are formed by ORAI1, ORAI2, and ORAI3 proteins and activated by stromal interaction molecule (STIM) 1 and STIM2. Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms.

Objective

We performed molecular and immunologic analysis of patients with CID, anhidrosis, and ectodermal dysplasia of unknown etiology.

Methods

We performed DNA sequencing of the ORAI1 gene, modeling of mutations on ORAI1 crystal structure, analysis of ORAI1 mRNA and protein expression, SOCE measurements, immunologic analysis of peripheral blood lymphocyte populations by using flow cytometry, and histologic and ultrastructural analysis of patient tissues.

Results

We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectodermal dysplasia with anhidrosis, and muscular dysplasia. The patients were homozygous for p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts. In addition to impaired T-cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer T and regulatory T (Treg) cells and altered composition of γδ T-cell and natural killer cell subsets.

Conclusion

ORAI1 null mutations are associated with reduced numbers of invariant natural killer T and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity. ORAI1-deficient patients have dental enamel defects and anhidrosis, representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency that is distinct from previously reported patients with anhidrotic ectodermal dysplasia with immunodeficiency caused by mutations in the nuclear factor κB signaling pathway (IKBKG and NFKBIA).

Le texte complet de cet article est disponible en PDF.

Graphical abstract

Le texte complet de cet article est disponible en PDF.

Key words : Ca²⁺ release–activated Ca²⁺ channel, store-operated Ca²⁺ entry, calcium, ORAI1, T cells, regulatory T cells, invariant natural killer T cells, immunodeficiency, combined immunodeficiency, anhidrotic ectodermal dysplasia

Abbreviations used : AIHA, ANA, AR, CID, CMV, CRAC, dOrai, EDA, EDA-ID, EM, ER, FOXP3, GAPDH, HD, H&E, HSCT, iNKT, IP₃, NF-κB, NK, PAS, RSV, SOCE, STIM, TCR, TM, Treg, UCS

Plan

Time-lapse Ca²⁺ imaging

Results

Identification of patients with novel mutations in ORAI1

Modeling of ORAI1 mutations on the crystal structure of Drosophila melanogaster Orai

ORAI1 mutations abolish SOCE and protein expression

ORAI1 mutations impair T-cell function and perturb iNKT, NK, Treg, and γδ T-cell populations

ORAI1 null mutations cause EDA

Discussion

Supported by National Institutes of Health grants AI097302 (to S.F.), and AI065303 (to D.U.), postdoctoral fellowships KA 4514/1-1 (to S.K.) and VA 882/1-1 (to M.V.) by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG), and BMBF grant 01 EO0803 by the German Federal Ministry of Education and Research (to S.E. and C.S.).

Disclosure of potential conflict of interest: I. Kacskovics is founder and CEO of ImmunoGenes and has the following patents: issued—European Union: EP 2 097 444 B1, Hong Kong: 2007323049, Australia: AU2007323049, Canada: CA2670389, China: CN101595128 A, and Japan: JP2010510773 (A); pending—USPTO: 12515586. S. Feske is a cofounder of Calcimedica and a coinventor on the following issued patent: WO/2007/081804. The rest of the authors declare that they have no relevant conflicts of interest.

Export

Vol 142 - N° 4

P. 1297 - octobre 2018 Retour au numéro

Article précédent

Loss-of-function nuclear factor ?B subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans
Paul Tuijnenburg, Hana Lango Allen, Siobhan O. Burns, Daniel Greene, Machiel H. Jansen, Emily Staples, Jonathan Stephens, Keren J. Carss, Daniele Biasci, Helen Baxendale, Moira Thomas, Anita Chandra, Sorena Kiani-Alikhan, Hilary J. Longhurst, Suranjith L. Seneviratne, Eric Oksenhendler, Ilenia Simeoni, Godelieve J. de Bree, Anton T.J. Tool, Ester M.M. van Leeuwen, Eduard H.T.M. Ebberink, Alexander B. Meijer, Salih Tuna, Deborah Whitehorn, Matthew Brown, Ernest Turro, Adrian J. Thrasher, Kenneth G.C. Smith, James E. Thaventhiran, Taco W. Kuijpers

| Article suivant

PD-1 blocks lytic granule polarization with concomitant impairment of integrin outside-in signaling in the natural killer cell immunological synapse
Yu Huang, Zhiying Chen, Joon Hee Jang, Mirza S. Baig, Grant Bertolet, Casey Schroeder, Shengjian Huang, Qian Hu, Yong Zhao, Dorothy E. Lewis, Lidong Qin, Michael Xi Zhu, Dongfang Liu

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

connectez-vous ou créez un compte

ORAI1 mutations abolishing store-operated Ca²⁺ entry cause anhidrotic ectodermal dysplasia with immunodeficiency - 05/10/18

Abstract

Background

Objective

Methods

Results

Conclusion

Graphical abstract

Plan

Export citations

Fichier

Contenu

Accès rapides

Mon compte

Aide & support

Plateformes Elsevier Masson

Déclaration CNIL