Human Germline Biallelic Loss-of-Function OSMR Variants Cause Severe Allergic Disease

IntroductionOSMR encodes oncostatin M receptor beta (OSMRβ), a cell surface receptor of the gp130 family that binds OSM and IL-31, and is highly expressed on fibroblasts. The gp130 family comprises signaling proteins, many of which have been linked to primary atopic disorders (PAD).MethodsWe have been performing genetic evaluations on patients with suspected PADs, and we have identified a cohort with biallelic variants in OSMR. Functionally, we defined the localization of OSMR variants in fibroblasts and in HEK293 cells using flow cytometry. We measured transcriptional signatures and protein signaling in patients’ fibroblasts after stimulation with IL-6 family cytokines. We linked OSMR genotype to phenotype using UK Biobank data.ResultsWe have now identified six probands from six different kindreds worldwide with biallelic, damaging OSMR variants, including a compound heterozygote p.[(V436D)];[(A349D)] and the following homozygous variants: p.(V436D) (n = 2), p.(Y660fs*16), p.(Q270*), and p.(Q51Tfs*23). All patients had a core phenotype of severe atopic dermatitis, peripheral eosinophilia, and markedly elevated serum IgE. The OSMR variants prevented OSMRβ from localizing to the cell surface, as demonstrated in patients’ fibroblasts and in HEK293 cells overexpressing the variants. Stimulation of fibroblasts with OSM resulted in decreased levels of pSTAT1 and pSTAT3; no decrease was noted after stimulation with IL-6 or IL-27. Inflammatory transcriptional signatures were noted in fibroblasts by RNA sequencing, which were restored by WT-OSMR transduction.The p.(V436D) variant has been reported in gnomAD (v4.1), with 14 homozygous individuals identified, 9 of whom are from the UK Biobank. We obtained clinical data from the UK Biobank, which showed that 7/9 (78%) individuals had either elevated eosinophil levels, allergic manifestations, or a skin phenotype. We systematically tested all homozygous coding OSMR variants reported in gnomAD with a minor allele frequency greater than the p.(V436D) variant (minor allele frequency [MAF]=0.00339). These population variants, localized to the cell surface at the same frequency as WT-OSMR, β and were predicted to be benign by AlphaMissense, unlike the patients’ OSMR variants.ConclusionWe expand our understanding of the role of OSMRβ in human health and disease by describing patients with biallelic loss-of-function variants in OSMR.