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

被引：66

作者：

Lian, Jayson ^{[1
]}

Cuk, Mario ^{[2
]}

Kahlfuss, Sascha ^{[1
]}

Kozhaya, Lina ^{[3
]}

Vaeth, Martin ^{[1
]}

Rieux-Laucat, Frederic ^{[4
,5
]}

Picard, Capucine ^{[5
,6
]}

Benson, Melina J. ^{[1
]}

Jakovcevic, Antonia ^{[7
]}

Bilic, Karmen ^{[8
]}

Martinac, Iva ^{[2
]}

Stathopulos, Peter ^{[9
]}

Kacskovics, Imre ^{[10
]}

Vraetz, Thomas ^{[11
]}

Speckmann, Carsten ^{[11
,12
]}

Ehl, Stephan ^{[11
,12
]}

Issekutz, Thomas ^{[13
]}

Unutmaz, Derya ^{[3
]}

Feske, Stefan ^{[1
]}

机构：

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

[2] Univ Zagreb, Sch Med, Univ Hosp Ctr Zagreb, Dept Pediat, Zagreb, Croatia

[3] Jackson Lab Genom Med, Farmington, CT USA

[4] INSERM, UMR 1163, Lab Immunogenet Pediat Autoimmune Dis, Paris, France

[5] Paris Descartes Sorbonne Paris Cite Univ, INSERM, Imagine Inst, UMR1163, Paris, France

[6] Necker Enfants Malad Hosp, AP HP, Necker Med Sch, Study Ctr Primary Immunodeficiencies, Paris, France

[7] Univ Hosp Ctr Zagreb, Dept Pathol & Cytol, Zagreb, Croatia

[8] Univ Hosp Ctr Zagreb, Dept Lab Diagnost, Zagreb, Croatia

[9] Western Univ, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, Canada

[10] ImmunoGenes, Budapest, Hungary

[11] Univ Freiburg, Fac Med, Med Ctr, Dept Pediat Hematol & Oncol,Ctr Pediat, Freiburg, Germany

[12] Univ Freiburg, Fac Med, Med Ctr, Ctr Chron Immunodeficiency, Freiburg, Germany

[13] Dalhousie Univ, Dept Pediat, Div Immunol, Halifax, NS, Canada

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2018年 / 142卷 / 04期

基金：

美国国家卫生研究院;

关键词：

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; T-CELL-RECEPTOR; TUBULAR AGGREGATE MYOPATHY; CALCIUM-ENTRY; CRAC CHANNEL; IMMUNE-DEFICIENCY; EFFECTOR FUNCTION; NK CELLS; STIM1; ACTIVATION; INFLUX;

D O I：

10.1016/j.jaci.2017.10.031

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

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 gamma delta 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 kappa B signaling pathway (IKBKG and NFKBIA).

引用

页码：1297 / +

页数：25

共 70 条

[1] Combined immunodeficiency due to a homozygous mutation in ORAI1 that deletes the C-terminus that interacts with STIM 1 [J].