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

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically linked to dominant-negative (DN) STAT3 mutations.
• Patients present with recurrent infections (Staphylococcus), mucocutaneous candidiasis, allergies, and skeletal issues.

Purpose of the Study:

• To investigate the role of IL6ST mutations in AD-HIES.
• To characterize the functional consequences of identified IL6ST mutations.

Main Methods:

• Genetic analysis of 12 patients from 8 kindreds with AD-HIES.
• Identification and characterization of IL6ST mutations.
• In vitro studies of mutant GP130 receptor function and cellular responses to cytokines (IL-6, IL-11, LIF, OSM).

Main Results:

• Identified seven distinct truncating IL6ST mutations in AD-HIES patients, one recurrent.
• Mutant IL6ST alleles encode GP130 receptors lacking STAT3-recruiting sites and a recycling motif.
• Mutant proteins accumulate on the cell surface, exhibiting loss-of-function and DN properties for IL-6, IL-11, LIF, and OSM signaling.
• Patient cells show impaired responses to IL-6 and IL-11.

Conclusions:

• DN IL6ST mutations are a cause of AD-HIES, presenting clinical phenotypes similar to STAT3 mutations.
• Impairment of IL-6 and IL-11 signaling pathways underlies the infectious, allergic, and skeletal manifestations observed in these patients.