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Human germline biallelic loss-of-function OSMR variants cause severe allergic disease
Journal article   Open access   Peer reviewed

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

Simran Samra, Mehul Sharma, Julia Körholz, Yihui Liu, Alyssa James, Christina Michalski, Pariya Yousefi, Kate L. Del Bel, Henry Y. Lu, Ashish A. Sharma, …
Journal of Human Immunity, Vol.2(4), e20260067
05/28/2026
DOI: 10.70962/jhi.20260067
PMCID: PMC13218299
PMID: 42221229
url
https://doi.org/10.70962/jhi.20260067View
Published (Version of record) Open Access

Abstract

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.
 Atopy Inborn Errors of Immunity

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