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

Area of Science:

• Immunology
• Genetics
• Dermatology

Background:

• Oncostatin M receptor beta (OSMRβ) is crucial for signaling by Oncostatin M (OSM) and IL-31.
• Atopic dermatitis is a complex inflammatory skin condition with significant genetic and environmental factors.

Purpose of the Study:

• To investigate the genetic basis of a severe, early-onset atopic dermatitis phenotype.
• To determine the functional consequences of identified genetic variants in OSMR.

Main Methods:

• Genetic analysis of affected individuals and families.
• Cellular assays to assess OSMRβ localization and signaling.
• Transcriptomic profiling of patient-derived cells.

Main Results:

• Identified biallelic loss-of-function variants in OSMR in patients with severe atopic dermatitis, eosinophilia, and elevated IgE.
• Patient-derived OSMRβ variants failed to reach the cell surface, impairing OSM signaling.
• Downstream effects included reduced STAT phosphorylation and altered inflammatory gene expression.

Conclusions:

• Biallelic OSMR deficiency is a newly identified primary genetic disorder underlying severe atopic dermatitis.
• OSMRβ is essential for normal immune responses in the skin and systemic inflammation.