Human germline biallelic loss-of-function OSMR variants cause severe allergic disease.
PMID 42221229 | PMCID PMC13218299 | DOI 10.70962/jhi.20260067 · Journal of human immunity · 2026
Oncostatin M (OSM) receptor beta (OSMRβ), encoded by OSMR, is a cytokine receptor subunit required for signaling by OSM and IL-31. We identified 10 affected individuals from seven unrelated families with germline biallelic loss-of-function variants in OSMR who shared a phenotype of early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. All patient-derived OSMRβ variants failed to localize to the cell surface, resulting in selective loss of OSM-dependent signaling. Patient cells showed markedly reduced OSM-induced phosphorylation of STAT1, STAT3, and STAT5, while signaling through other IL-6 family receptor complexes remained intact. Transcriptomic profiling of patient primary dermal fibroblasts revealed consistent downstream effects, including loss of interferon-responsive and inflammatory gene programs. Re-expression of wild-type OSMR restored receptor surface expression, STAT activation, and transcriptional responses, confirming a causal loss-of-function mechanism. Together, these findings establish biallelic OSMR deficiency as a novel primary atopic disorder.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | OSMR | “Human germline biallelic loss-of-function OSMR variants cause severe allergic disease.” | 0.98 | hgnc_dict_v1 |
| gene | STAT1 | “Patient cells showed markedly reduced OSM-induced phosphorylation of STAT1, STAT3, and STAT5, while signaling through other IL-6 family receptor complexes remained intact.” | 0.98 | hgnc_dict_v1 |
| gene | STAT3 | “Patient cells showed markedly reduced OSM-induced phosphorylation of STAT1, STAT3, and STAT5, while signaling through other IL-6 family receptor complexes remained intact.” | 0.98 | hgnc_dict_v1 |
| phenotype | atopic dermatitis | “We identified 10 affected individuals from seven unrelated families with germline biallelic loss-of-function variants in OSMR who shared a phenotype of early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE.” | 0.98 | phenotype_alias_lexicon_v2 |
| population | Population | “We identified 10 affected individuals from seven unrelated families with germline biallelic loss-of-function variants in OSMR who shared a phenotype of early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE.” | 0.80 | saudi_context_rules_v1 |