IFNAR1 and Immunodeficiency 106, Susceptibility to Viral Infections

Autosomal recessive deficiency of interferon alpha/beta receptor 1 (IFNAR1) underlies a rare inborn error of immunity characterized by severe susceptibility to live-attenuated vaccine and wild-type viruses. IFNAR1 encodes the IFNAR1 subunit of the type I IFN receptor complex required for antiviral signal transduction via STAT1/STAT2.

Seven children from five unrelated western Polynesian kindreds presented with life-threatening viral infections and were all homozygous for the same nonsense IFNAR1 variant, c.1156G>T (p.Glu386Ter) (PMID:35442418). This allele exhibits a minor allele frequency >1% in Samoa and is observed across Polynesian islands, consistent with a founder effect.

The inheritance mode is autosomal recessive, with heterozygous carriers clinically unaffected. Segregation of disease only in homozygotes across multiple families confirms the recessive model.

Functional studies demonstrate that p.Glu386Ter encodes a truncated IFNAR1 protein that fails to reach the cell surface and cannot transduce type I IFN signals; patient fibroblasts do not respond to IFN-α2, IFN-ω or IFN-β (PMID:35442418).

A tri-allelic PCR assay targeting rs201609461 (c.1156G>T and c.1156G>A) enables rapid identification of homozygotes and heterozygotes from dried blood spots, facilitating early diagnosis in remote regions (PMID:37973454).

Integration of genetic and functional data yields a strong gene-disease association. Screening for IFNAR1 p.Glu386Ter in individuals of Polynesian ancestry with severe viral illness is clinically actionable and supports prompt antiviral management.

References

• The Journal of experimental medicine • 2022 • A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes. PMID:35442418
• Pathology • 2024 • Detection of interferon alpha and beta receptor subunit 1 (IFNAR1) loss-of-function Glu386 variant by tri-allelic genotyping* PMID:37973454

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