@article {905,
	title = {Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.},
	journal = {J Exp Med},
	volume = {217},
	year = {2020},
	month = {2020 06 01},
	abstract = {<p>Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients{\textquoteright} heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.</p>},
	keywords = {Adolescent, Alleles, C-Reactive Protein, Cell Membrane, Cells, Cultured, Child, Cytokine Receptor gp130, Cytokines, Female, Fibroblasts, Genes, Dominant, Genetics, Population, HEK293 Cells, Humans, Job Syndrome, Kinetics, Loss of Function Mutation, Male, Middle Aged, Models, Biological, Mutation, Pedigree, Phenotype, Th2 Cells, Up-Regulation, Young Adult},
	issn = {1540-9538},
	doi = {10.1084/jem.20191804},
	author = {B{\'e}ziat, Vivien and Tavernier, Simon J and Chen, Yin-Huai and Ma, Cindy S and Materna, Marie and Laurence, Arian and Staal, Jens and Aschenbrenner, Dominik and Roels, Lisa and Worley, Lisa and Claes, Kathleen and Gartner, Lisa and Kohn, Lisa A and De Bruyne, Marieke and Schmitz-Abe, Klaus and Charbonnier, Louis-Marie and Keles, Sevgi and Nammour, Justine and Vladikine, Natasha and Maglorius Renkilaraj, Majistor Raj Luxman and Seeleuthner, Yoann and Migaud, M{\'e}lanie and Rosain, J{\'e}r{\'e}mie and Jeljeli, Mohamed and Boisson, Bertrand and Van Braeckel, Eva and Rosenfeld, Jill A and Dai, Hongzheng and Burrage, Lindsay C and Murdock, David R and Lambrecht, Bart N and Avettand-Fenoel, V{\'e}ronique and Vogel, Tiphanie P and Esther, Charles R and Haskologlu, Sule and Dogu, Figen and Ciznar, Peter and Boutboul, David and Ouach{\'e}e-Chardin, Marie and Amourette, Jean and Lebras, Marie-No{\"e}lle and Gauvain, Cl{\'e}ment and Tcherakian, Colas and Ikinciogullari, Aydan and Beyaert, Rudi and Abel, Laurent and Milner, Joshua D and Grimbacher, Bodo and Couderc, Louis-Jean and Butte, Manish J and Freeman, Alexandra F and Catherinot, Emilie and Fieschi, Claire and Chatila, Talal A and Tangye, Stuart G and Uhlig, Holm H and Haerynck, Filomeen and Casanova, Jean-Laurent and Puel, Anne}
}
@article {215,
	title = {Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.},
	journal = {Blood},
	volume = {125},
	year = {2015},
	month = {2015 Jan 22},
	pages = {591-9},
	abstract = {<p>Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as $\#$NCT00001350. </p>},
	keywords = {Adolescent, Adult, Autoimmune Diseases, Child, Child, Preschool, Female, Genetic Diseases, Inborn, Humans, Infant, Lymphoproliferative Disorders, Male, Mutation, Phosphorylation, STAT1 Transcription Factor, STAT3 Transcription Factor, STAT5 Transcription Factor, T-Lymphocytes, Regulatory},
	issn = {1528-0020},
	doi = {10.1182/blood-2014-09-602763},
	author = {Milner, Joshua D and Vogel, Tiphanie P and Forbes, Lisa and Ma, Chi A and Stray-Pedersen, Asbj{\o}rg and Niemela, Julie E and Lyons, Jonathan J and Engelhardt, Karin R and Zhang, Yu and Topcagic, Nermina and Roberson, Elisha D O and Matthews, Helen and Verbsky, James W and Dasu, Trivikram and Vargas-Hernandez, Alexander and Varghese, Nidhy and McClain, Kenneth L and Karam, Lina B and Nahmod, Karen and Makedonas, George and Mace, Emily M and Sorte, Hanne S and Perminow, G{\o}ri and Rao, V Koneti and O{\textquoteright}Connell, Michael P and Price, Susan and Su, Helen C and Butrick, Morgan and McElwee, Joshua and Hughes, Jason D and Willet, Joseph and Swan, David and Xu, Yaobo and Santibanez-Koref, Mauro and Slowik, Voytek and Dinwiddie, Darrell L and Ciaccio, Christina E and Saunders, Carol J and Septer, Seth and Kingsmore, Stephen F and White, Andrew J and Cant, Andrew J and Hambleton, Sophie and Cooper, Megan A}
}
