Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome - Archive ouverte HAL Access content directly
Journal Articles Journal of Experimental Medicine Year : 2020

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

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Jill A. Rosenfeld
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  • PersonId : 906001
Clément Gauvain
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Filomeen Haerynck
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  • PersonId : 892234

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.

Dates and versions

hal-02549533 , version 1 (21-04-2020)

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Vivien Beziat, Simon Tavernier, Yin-Huai Chen, Cindy Ma, Marie Materna, et al.. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. Journal of Experimental Medicine, 2020, 217 (6), ⟨10.1084/jem.20191804⟩. ⟨hal-02549533⟩
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