STAT3 mutations in the hyper-IgE syndrome.

@article{citeulike:3021388, abstract = {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-gamma, had higher tumor necrosis factor alpha 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.}, address = {National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. smh@nih.gov}, author = {Holland, S. M. and DeLeo, F. R. and Elloumi, H. Z. and Hsu, A. P. and Uzel, G. and Brodsky, N. and Freeman, A. F. and Demidowich, A. and Davis, J. and Turner, M. L. and Anderson, V. L. and Darnell, D. N. and Welch, P. A. and Kuhns, D. B. and Frucht, D. M. and Malech, H. L. and Gallin, J. I. and Kobayashi, S. D. and Whitney, A. R. and Voyich, J. M. and Musser, J. M. and Woellner, C. and Sch\"{a}ffer, A. A. and Puck, J. M. and Grimbacher, B. }, citeulike-article-id = {3021388}, doi = {http://dx.doi.org/10.1056/NEJMoa073687}, issn = {1533-4406}, journal = {The New England journal of medicine}, keywords = {hige}, month = {October}, number = {16}, pages = {1608--1619}, posted-at = {2008-07-19 23:11:43}, priority = {2}, title = {STAT3 mutations in the hyper-IgE syndrome.}, url = {http://dx.doi.org/10.1056/NEJMoa073687}, volume = {357}, year = {2007} }

TY - JOUR ID - citeulike:3021388 L3 - citeulike-article-id:3021388 TI - STAT3 mutations in the hyper-IgE syndrome. JF - The New England journal of medicine VL - 357 IS - 16 SP - 1608 EP - 1619 AD - National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. smh@nih.gov SN - 1533-4406 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-gamma, had higher tumor necrosis factor alpha 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. KW - hige AU - Holland, SM AU - DeLeo, FR AU - Elloumi, HZ AU - Hsu, AP AU - Uzel, G AU - Brodsky, N AU - Freeman, AF AU - Demidowich, A AU - Davis, J AU - Turner, ML AU - Anderson, VL AU - Darnell, DN AU - Welch, PA AU - Kuhns, DB AU - Frucht, DM AU - Malech, HL AU - Gallin, JI AU - Kobayashi, SD AU - Whitney, AR AU - Voyich, JM AU - Musser, JM AU - Woellner, C AU - Schäffer, AA AU - Puck, JM AU - Grimbacher, B PY - 2007/10/18/ UR - http://dx.doi.org/10.1056/NEJMoa073687 ER -