TY - JOUR
T1 - STAT3 mutations in the hyper-IgE syndrome
AU - Holland, Steven M.
AU - DeLeo, Frank R.
AU - Elloumi, Houda Z.
AU - Hsu, Amy P.
AU - Uzel, Gulbu
AU - Brodsky, Nina
AU - Freeman, Alexandra F.
AU - Demidowich, Andrew
AU - Davis, Joie
AU - Turner, Maria L.
AU - Anderson, Victoria L.
AU - Darnell, Dirk N.
AU - Welch, Pamela A.
AU - Kuhns, Douglas B.
AU - Frucht, David M.
AU - Malech, Harry L.
AU - Gallin, John I.
AU - Kobayashi, Scott D.
AU - Whitney, Adeline R.
AU - Voyich, Jovanka M.
AU - Musser, James M.
AU - Woellner, Cristina
AU - Schäffer, Alejandro A.
AU - Puck, Jennifer M.
AU - Grimbacher, Bodo
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2007/10/18
Y1 - 2007/10/18
N2 - BACKGROUND: The hyper-IgE syndrome (or Job's syndrome) is a rare disorder of immunity and connective tissue characterized by dermatitis, boils, cyst-forming pneumonias, elevated serum IgE levels, retained primary dentition, and bone abnormalities. Inheritance is autosomal dominant; sporadic cases are also found. METHODS: We collected longitudinal clinical data on patients with the hyper-IgE syndrome and their families and assayed the levels of cytokines secreted by stimulated leukocytes and the gene expression in resting and stimulated cells. These data implicated the signal transducer and activator of transcription 3 gene (STAT3) as a candidate gene, which we then sequenced. RESULTS: We found increased levels of proinflammatory gene transcripts in unstimulated peripheral-blood neutrophils and mononuclear cells from patients with the hyper-IgE syndrome, as compared with levels in control cells. In vitro cultures of mononuclear cells from patients that were stimulated with lipopolysaccharide, with or without interferon-γ, had higher tumor necrosis factor α levels than did identically treated cells from unaffected persons (P = 0.003). In contrast, the cells from patients with the hyper-IgE syndrome generated lower levels of monocyte chemoattractant protein 1 in response to the presence of interleukin-6 (P = 0.03), suggesting a defect in interleukin-6 signaling through its downstream mediators, one of which is STAT3. We identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of the hyper-IgE syndrome. Eighteen discrete mutations, five of which were hot spots, were predicted to directly affect the DNA-binding and SRC homology 2 (SH2) domains. CONCLUSIONS: Mutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome, an immunodeficiency syndrome involving increased innate immune response, recurrent infections, and complex somatic features.
AB - BACKGROUND: The hyper-IgE syndrome (or Job's syndrome) is a rare disorder of immunity and connective tissue characterized by dermatitis, boils, cyst-forming pneumonias, elevated serum IgE levels, retained primary dentition, and bone abnormalities. Inheritance is autosomal dominant; sporadic cases are also found. METHODS: We collected longitudinal clinical data on patients with the hyper-IgE syndrome and their families and assayed the levels of cytokines secreted by stimulated leukocytes and the gene expression in resting and stimulated cells. These data implicated the signal transducer and activator of transcription 3 gene (STAT3) as a candidate gene, which we then sequenced. RESULTS: We found increased levels of proinflammatory gene transcripts in unstimulated peripheral-blood neutrophils and mononuclear cells from patients with the hyper-IgE syndrome, as compared with levels in control cells. In vitro cultures of mononuclear cells from patients that were stimulated with lipopolysaccharide, with or without interferon-γ, had higher tumor necrosis factor α levels than did identically treated cells from unaffected persons (P = 0.003). In contrast, the cells from patients with the hyper-IgE syndrome generated lower levels of monocyte chemoattractant protein 1 in response to the presence of interleukin-6 (P = 0.03), suggesting a defect in interleukin-6 signaling through its downstream mediators, one of which is STAT3. We identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of the hyper-IgE syndrome. Eighteen discrete mutations, five of which were hot spots, were predicted to directly affect the DNA-binding and SRC homology 2 (SH2) domains. CONCLUSIONS: Mutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome, an immunodeficiency syndrome involving increased innate immune response, recurrent infections, and complex somatic features.
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U2 - 10.1056/NEJMoa073687
DO - 10.1056/NEJMoa073687
M3 - Article
C2 - 17881745
AN - SCOPUS:35348960378
VL - 357
SP - 1608
EP - 1619
JO - New England Journal of Medicine
JF - New England Journal of Medicine
SN - 0028-4793
IS - 16
ER -