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

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dc.contributor.authorÖZEN, AHMET OĞUZHAN
dc.contributor.authorsBaris, Safa; Alroqi, Fayhan; Kiykim, Ayca; Karakoc-Aydiner, Elif; Ogulur, Ismail; Ozen, Ahmet; Charbonnier, Louis-Marie; Bakir, Mustafa; Boztug, Kaan; Chatila, Talal A.; Barlan, Isil B.
dc.date.accessioned2022-03-14T08:14:42Z
dc.date.available2022-03-14T08:14:42Z
dc.date.issued2016-10
dc.description.abstractLoss 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). Clinical data and laboratory findings including immunophenotyping, level of interferon (IFN)-gamma/IL-17(+) T cells, interferon-induced STAT1 phosphorylation, and JAK inhibitor assays were evaluated. Sequencing of STAT1 gene was performed by Sanger sequencer. 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-gamma and decreased IL-17 expression as compared to controls. They also exhibited increased IFN-beta and -gamma-induced STAT1 phosphorylation that was reversed upon treatment with the JAK kinase inhibitor ruxolitinib. 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.
dc.identifier.doi10.1007/s10875-016-0312-3
dc.identifier.eissn1573-2592
dc.identifier.issn0271-9142
dc.identifier.pubmed27379765
dc.identifier.urihttps://hdl.handle.net/11424/241272
dc.identifier.wosWOS:000383246400006
dc.language.isoeng
dc.publisherSPRINGER/PLENUM PUBLISHERS
dc.relation.ispartofJOURNAL OF CLINICAL IMMUNOLOGY
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectSTAT1
dc.subjectgain-of-function mutation
dc.subjectmucocutaneous candidiasis
dc.subjectcombined immunodeficiency
dc.subjectautoimmunity
dc.subjectruxolitinib
dc.subjectCHRONIC MUCOCUTANEOUS CANDIDIASIS
dc.subjectSIGNAL TRANSDUCER
dc.subjectINBORN-ERRORS
dc.subjectIMMUNITY
dc.subjectDEFICIENCY
dc.subjectACTIVATOR
dc.titleSevere Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1
dc.typearticle
dspace.entity.typePublication
local.avesis.id9884af5f-7727-434c-aa56-4fcac22533e2
local.import.packageSS16
local.indexed.atWOS
local.indexed.atSCOPUS
local.indexed.atPUBMED
local.journal.numberofpages8
local.journal.quartileQ2
oaire.citation.endPage648
oaire.citation.issue7
oaire.citation.startPage641
oaire.citation.titleJOURNAL OF CLINICAL IMMUNOLOGY
oaire.citation.volume36
relation.isAuthorOfPublication3e9c297b-e636-4836-8f61-dc9c8b7c29cf
relation.isAuthorOfPublication.latestForDiscovery3e9c297b-e636-4836-8f61-dc9c8b7c29cf

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