Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome
Gulbu Uzel, Elizabeth P Sampaio, Monica G Lawrence, Amy P Hsu, Mary Hackett, Morna J Dorsey, Richard J Noel, James W Verbsky, Alexandra F Freeman, Erin Janssen, Francisco A Bonilla, Joseph Pechacek, Prabha Chandrasekaran, Sarah K Browne, Anahita Agharahimi, Ahmed M Gharib, Sara C Mannurita, Jae Joon Yim, Eleonora Gambineri, Troy Torgerson, Dat Q Tran, Joshua D Milner, Steven M Holland, Gulbu Uzel, Elizabeth P Sampaio, Monica G Lawrence, Amy P Hsu, Mary Hackett, Morna J Dorsey, Richard J Noel, James W Verbsky, Alexandra F Freeman, Erin Janssen, Francisco A Bonilla, Joseph Pechacek, Prabha Chandrasekaran, Sarah K Browne, Anahita Agharahimi, Ahmed M Gharib, Sara C Mannurita, Jae Joon Yim, Eleonora Gambineri, Troy Torgerson, Dat Q Tran, Joshua D Milner, Steven M Holland
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.
Published by Mosby, Inc.
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Source: PubMed