Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative mutations in STAT3. The patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, an allergic triad (elevated serum IgE, eosinophilia, and eczema) and extra-hematopoietic manifestations, mostly affecting the skeleton.
We studied 7 patients from 3 unrelated kindred with AD-HIES
We found two heterozygous mutations in IL6ST (I719fs and T761fs), one of which (I719fs) is shared by two unrelated kindreds including one in which it occurred de novo. The two mutant alleles encode truncated GP130 proteins that retain the transmembrane domain, but lack both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the two mutant proteins are loss-of-function for cellular responses to IL-6, IL-11, LIF, and OSM, and hypomorphic for IL-27. They also accumulate at the cell surface and exert a potent dominant-negative effect for cellular responses to IL-6, IL-11, IL-27, LIF and OSM. The patients’ PBMCs and fibroblasts respond poorly to IL-6, IL-11, and IL-27. Like STAT3-mutated patients, IL6ST-mutated patients have infectious and allergic phenotypes seen in complete IL-6R deficiency, and skeletal anomalies seen in complete IL-11R deficiency.
Dominant-negative STAT3 and IL6ST mutations underlie clinical phenocopies by impairing IL-6 and IL-11 responsive pathways.