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

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.

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

“…Moreover, the viral phenotypes of patient fibroblasts were not rescued by treatment with IFN-a2b or -b, further confirming a complete IFNAR1 deficiency. Complete cytokine receptor deficiency due to the expression at the cell surface of a non-functional receptor has already been documented for IFNGR1, IFNGR2, IL17RA, IL10RA, IL10RB, IL6ST, and IL12RB1, with mutations impairing cytokine binding(56,(74)(75)(76)(77)(78)(79)(80). By contrast to these previous observations, the mutant IFNAR1 reported here is loss-of-function due to the absence of most of its intracellular domain, abolishing its signaling activity.…”

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

“…This premise could account for the increased ERK signaling seen in IL6RA mutant mice, perhaps reflecting increased IL11-driven ERK signaling 3 . The idea of diminished interaction of mutant alpha chains with gp130 is suggested further by human genetics: autosomal recessive mutations in gp130 are associated with craniosynostosis, whereas autosomal dominant variation is not 19,20 .…”

Clinical Profile of Hyper-IgE Syndrome in India

“…All 27 patients harbored rare variants in the STAT3 gene: eight in exon 21; eight in exon 13; three in exon 10; two in exon 15, and one each in exon 6,16,17,19,22, and splice site downstream of exon 12 (Figure 1, Supplementary Table 1). Of these, three were picked up by whole exome sequencing, 16 by the 320 gene NGS panel, one by the limited 44 gene NGS panel, and seven by Sanger sequencing for STAT3 gene (Supplementary Table 2).…”

“…TH17 cell numbers were low in 10/11 (90.9%) STAT3 HIES tested. Rare variants observed were 8 in exon 21; 8 in exon 13; 3 in exon 10; 2 in exon 15, and one each in exon 6,16,17,19,22, and splice site downstream of exon 12. Seven variants were novel and included F174S, N567D, L404Sfs * 8, G419 =, M329K, T714I, R518X, and a splice site variant downstream of exon 12.…”