Top

Published in:

01-10-2016 | Original Article

Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1

Authors: Safa Baris, Fayhan Alroqi, Ayca Kiykim, Elif Karakoc-Aydiner, Ismail Ogulur, Ahmet Ozen, Louis-Marie Charbonnier, Mustafa Bakır, Kaan Boztug, Talal A. Chatila, Isil B. Barlan

Published in: Journal of Clinical Immunology | Issue 7/2016

Abstract

Purpose

Loss and gain-of-function (GOF) mutations in human signal transducer and activator of transcription 1 (STAT1) lead to distinct phenotypes. Although recurrent infections are common to both types of STAT1 mutations, GOF mutations are distinguished by chronic mucocutaneous candidiasis and autoimmunity. However, the clinical spectra of STAT1 GOF mutations continue to expand. We here describe two patients with STAT1 GOF mutations presenting early in life with combined immunodeficiency (CID).

Methods

Clinical data and laboratory findings including immunophenotyping, level of interferon (IFN)-γ/IL-17⁺ T cells, interferon-induced STAT1 phosphorylation, and JAK inhibitor assays were evaluated. Sequencing of STAT1 gene was performed by Sanger sequencer.

Results

Patient 1 (P1) had persistent oral candidiasis and cytomegalovirus (CMV) infection since 2 months of age and later developed cavitary lung lesions due to Mycobacterium tuberculosis. Patient 2 (P2) presented with oral candidiasis and recurrent pneumonia at 4 months of age and subsequently developed CMV pneumonitis. Both patients suffered heterozygous missense mutations in STAT1, leading to deleterious amino acid substitutions in the DNA binding domain (P1: c.1154C > T; p.T385M; P2. c.971G > T; p.C324F). Circulating CD4⁺ T cells of both patients exhibited increased interferon-γ and decreased IL-17 expression as compared to controls. They also exhibited increased IFN-β and -γ-induced STAT1 phosphorylation that was reversed upon treatment with the JAK kinase inhibitor ruxolitinib.

Conclusion

STAT1 GOF mutations may present early in life with CID, consistent with the clinical heterogeneity of the disease. JAK kinase inhibitors may potentially be useful in some patients as adjunct therapy pending definitive treatment with bone marrow transplantation.

Casanova JL, Holland SM, Notarangelo LD. Inborn errors of human JAKs and STATs. Immunity. 2012;36(4):515–28. Pubmed Central PMCID: 3334867.CrossRefPubMedPubMedCentral

Dupuis S, Dargemont C, Fieschi C, Thomassin N, Rosenzweig S, Harris J, et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science. 2001;293(5528):300–3.CrossRefPubMed

Dupuis S, Jouanguy E, Al-Hajjar S, Fieschi C, Al-Mohsen IZ, Al-Jumaah S, et al. Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet. 2003;33(3):388–91.CrossRefPubMed

Boisson-Dupuis S, Kong XF, Okada S, Cypowyj S, Puel A, Abel L, et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol. 2012;24(4):364–78. Pubmed Central PMCID: 3477860.CrossRefPubMedPubMedCentral

van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011;365(1):54–61.CrossRefPubMed

Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208(8):1635–48. Pubmed Central PMCID: 3149226.CrossRefPubMedPubMedCentral

Hori T, Ohnishi H, Teramoto T, Tsubouchi K, Naiki T, Hirose Y, et al. Autosomal-dominant chronic mucocutaneous candidiasis with STAT1-mutation can be complicated with chronic active hepatitis and hypothyroidism. J Clin Immunol. 2012;32(6):1213–20.CrossRefPubMed

Marodi L, Cypowyj S, Toth B, Chernyshova L, Puel A, Casanova JL. Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species. J Allergy Clin Immunol. 2012;130(5):1019–27. Pubmed Central PMCID: 3703675.CrossRefPubMedPubMedCentral

Salzer E, Santos-Valente E, Klaver S, Ban SA, Emminger W, Prengemann NK, et al. B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C delta. Blood. 2013;121(16):3112–6. Pubmed Central PMCID: 3630826.CrossRefPubMedPubMedCentral

10.

Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML, et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013;131(6):1624–34. Pubmed Central PMCID: 3746066.CrossRefPubMedPubMedCentral

11.

Dotta L, Scomodon O, Padoan R, Timpano S, Plebani A, Soresina A, et al. Clinical and immunological data of nine patients with chronic mucocutaneous candidiasis disease. Data Brief. 2016;7:311–5. Pubmed Central PMCID: 4777981.CrossRefPubMedPubMedCentral

12.

Soltesz B, Toth B, Shabashova N, Bondarenko A, Okada S, Cypowyj S, et al. New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe. J Med Genet. 2013;50(9):567–78. Pubmed Central PMCID: 3756505.CrossRefPubMedPubMedCentral

13.

Higgins E, Al Shehri T, McAleer MA, Conlon N, Feighery C, Lilic D, et al. Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis caused by gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation. J Allergy Clin Immunol. 2015;135(2):551–3.CrossRefPubMed

14.

Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371(6):507–18. Pubmed Central PMCID: 4174543.CrossRefPubMedPubMedCentral

15.

Uzel G, Sampaio EP, Lawrence MG, Hsu AP, Hackett M, Dorsey MJ, et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol. 2013;131(6):1611–23. Pubmed Central PMCID: 3672257.CrossRefPubMedPubMedCentral

16.

Sobh A, Chou J, Schneider L, Geha RS, Massaad MJ. Chronic mucocutaneous candidiasis associated with an SH2 domain gain-of-function mutation that enhances STAT1 phosphorylation. J Allergy Clin Immunol 2016

17.

Sharfe N, Nahum A, Newell A, Dadi H, Ngan B, Pereira SL, et al. Fatal combined immunodeficiency associated with heterozygous mutation in STAT1. J Allergy Clin Immunol. 2014;133(3):807–17.CrossRefPubMed

18.

Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype: an international survey of 274 patients from 167 kindreds. Blood 2016

19.

Mizoguchi Y, Tsumura M, Okada S, Hirata O, Minegishi S, Imai K, et al. Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis. J Leukoc Biol. 2014;95(4):667–76. Pubmed Central PMCID: 3958742.CrossRefPubMedPubMedCentral

20.

Aldave JC, Cachay E, Nunez L, Chunga A, Murillo S, Cypowyj S, et al. A 1-year-old girl with a gain-of-function STAT1 mutation treated with hematopoietic stem cell transplantation. J Clin Immunol. 2013;33(8):1273–5.CrossRefPubMed

Title: Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1
Authors: Safa Baris
Fayhan Alroqi
Ayca Kiykim
Elif Karakoc-Aydiner
Ismail Ogulur
Ahmet Ozen
Louis-Marie Charbonnier
Mustafa Bakır
Kaan Boztug
Talal A. Chatila
Isil B. Barlan
Publication date: 01-10-2016
Publisher: Springer US
Published in: Journal of Clinical Immunology / Issue 7/2016
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-016-0312-3

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 7/2016

Magnetic Resonance Imaging of Lungs as a Radiation-Free Technique for Lung Pathologies in Immunodeficient patients

Treatment of CGD-associated Colitis with the IL-23 Blocker Ustekinumab

Efficacy, Safety, and Pharmacokinetics of a Novel Human Immune Globulin Subcutaneous, 20 % in Patients with Primary Immunodeficiency Diseases in North America

Leukocyte Adhesion Deficiency Type 1 (LAD1) with Expressed but Nonfunctional CD11/CD18

Long-Term Outcomes of Hematopoietic Stem Cell Transplantation for ZAP70 Deficiency

Exploring Autoimmunity in a Cohort of Children with Genetically Confirmed Aicardi–Goutières Syndrome

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials