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J Allergy Clin Immunol. 2018 Oct;142(4):1297-1310.e11. doi: 10.1016/j.jaci.2017.10.031. Epub 2017 Nov 16.

ORAI1 mutations abolishing store-operated Ca2+ entry cause anhidrotic ectodermal dysplasia with immunodeficiency.

Author information

1
Department of Pathology, New York University School of Medicine, New York, NY.
2
Department of Pediatrics, University Hospital Centre Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia.
3
Jackson Laboratory for Genomic Medicine, Farmington, Conn.
4
INSERM UMR 1163, Laboratory of the Immunogenetics of Pediatric Autoimmune Diseases, Paris, France; INSERM UMR1163, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
5
INSERM UMR1163, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France; Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), Necker Medical School, Paris, France.
6
Department of Pathology and Cytology, University Hospital Centre Zagreb, Zagreb, Croatia.
7
Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia.
8
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
9
ImmunoGenes, Budapest, Hungary.
10
Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
11
Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
12
Division of Immunology, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
13
Department of Pathology, New York University School of Medicine, New York, NY. Electronic address: feskes01@nyumc.org.

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).

KEYWORDS:

Ca(2+) release–activated Ca(2+) channel; ORAI1; T cells; anhidrotic ectodermal dysplasia; calcium; combined immunodeficiency; immunodeficiency; invariant natural killer T cells; regulatory T cells; store-operated Ca(2+) entry

PMID:
29155098
PMCID:
PMC5955830
[Available on 2019-10-01]
DOI:
10.1016/j.jaci.2017.10.031

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