Human germline biallelic loss-of-function OSMR variants cause severe allergic disease

We identified probands from four kindreds with biallelic damaging variants in OSMR, which encodes OSMRβ. Patients had a unifying phenotype for severe widespread, early-onset atopic dermatitis, peripheral eosinophilia, and elevated serum IgE.

Patient OSMRβ variants were not appropriately expressed on the cell surface compared to OSMRβWT. Patient OSMR variants showed significantly reduced OSM-mediated activation of STAT1, STAT3, and STAT5 and distinct transcriptional changes in primary dermal fibroblasts, including loss of interferon and inflammatory signatures. These defects were rescued upon lentiviral transduction of WT-OSMR.