期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 217, 期 6, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20191804
关键词
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资金
- St. Giles Foundation
- Rockefeller University
- Institut National de la Sante et de la Recherche Medicale
- Paris Descartes University
- Howard Hughes Medical Institute
- Job Research Foundation
- French National Research Agency under the Investissement d'avenir program [ANR-10-IAHU-01]
- GENMSMD project [ANR-16-CE17-0005-01]
- LTh-MSMD-CMCD project [ANR-18-CE93-0008-01]
- PNEUMOPID project [ANR 14-CE15-0009-01]
- HGDIFD project [ANR-14-CE15-0006-01]
- French Foundation for Medical Research [EQU201903007798]
- Jeffrey Model Foundation
- Yale Center for Mendelian Genomics - National Human Genome Research Institute [UM1HG006504]
- National Heart, Lung, and Blood Institute
- GSP Coordinating Center [U24 HG008956]
- NIH [R01AI127564, R01AI128976]
- National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Award program [UL1 TR001866]
- University Hospital Ghent Spearhead Initiative for Immunology Research
- Grand Challenges Program of VIB
- Flemish Government [VR 2016 2312 Doc.1521/4]
- Deutsche Forschungsgemeinschaft [SFB1160/2_B5, CIBSS - EXC-2189, 390939984, RESIST - EXC 2155, 39087428]
- European Joint Programme on Rare Diseases of the European Union [GR1617/14-1/iPAD]
- Bundesministerium fur Bildung und Forschung [GAIN_ 01GM1910A]
- university research grant (BOF-University Ghent)
- French National Research Agency [NKIRP-ANR-13-PDOC-0025-01]
- National Health and Medical Research Council of Australia
- Biomedical Research Centre BRC Oxford
- Celgene
- NIH Common Fund through the Office of Strategic Coordination/Office of the NIH [U01HG007709]
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' 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.
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