Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

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Abstract: 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

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Notes: Journal of experimental medicine. - 217, 6 (2020) , e20191804, ISSN: 1540-9538

Event: Veröffentlichung

(where): Freiburg

(who): Universität

(when): 2020

Creator: Béziat, Vivien
Grimbacher, Bodo
Casanova, Jean-Laurent
Puel, Anne

DOI: 10.1084/jem.20191804

URN: urn:nbn:de:bsz:25-freidok-1660682

Rights: Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 25.03.2025, 1:45 PM CET

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Associated

Béziat, Vivien
Grimbacher, Bodo
Casanova, Jean-Laurent
Puel, Anne
Universität

Time of origin

2020

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Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

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Other Objects (12)

Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity

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