Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation–polyendocrinopathy–enteropathy–X-linked–like syndrome - 30/05/13
Abstract |
Background |
Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers.
Objective |
We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC.
Methods |
We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation–polyendocrinopathy–enteropathy–X-linked (IPEX)–like phenotype for STAT1 mutations.
Results |
We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4+ IL-17–producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4+ T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2–induced STAT5 phosphorylation.
Conclusions |
Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.
Le texte complet de cet article est disponible en PDF.Key words : Signal transducer and activator of transcription 1, immune dysregulation–polyendocrinopathy–enteropathy–X-linked, forkhead box protein 3, regulatory T cell, chronic mucocutaneous candidiasis, aneurysms
Abbreviations used : APC, CFSE, CMC, FOXP3, GAS, IPEX, IVIG, RSV, STAT1, Treg, WT
Plan
| Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases/National Institutes of Health and in part by the National Cancer Institute, National Institutes of Health (contract no. HHSN261200800001E), Bethesda, Maryland. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. |
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| Disclosure of potential conflict of interest: E. P. Sampaio has received grants from the National Institutes of Health and is employed by Medical Science and Computing. M. J. Dorsey has received grants from CSL Behring. J. W. Verbsky has received lecture fees from Baxter. F. A. Bonilla has received consultancy fees from CSL Behring, Immune Deficiency Foundation, American Research Group, and Grifols; is employed by the US Food and Drug Administration; has received lecture fees from New England Regional Genetics Group; and has received royalties from UpToDate. T. Torgerson has received grants from the National Institutes of Health, Baxter Biosciences, and CSL Behring; has consultant arrangements with and receives payment for lectures and development of educational presentations from Baxter Biosciences; and receives royalties from New England Biolabs. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 6
P. 1611 - juin 2013 Retour au numéro
Article précédent
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