Research ArticleIMMUNODEFICIENCY

Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency

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Science Immunology  18 Jun 2021:
Vol. 6, Issue 60, eabf9564
DOI: 10.1126/sciimmunol.abf9564

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Mutated OAS1 leads to immunodeficiency

Inborn errors of immunity can result in autoinflammatory immunodeficiencies. Type I interferon–inducible oligoadenylate synthetase 1 (OAS1) can initiate antiviral immune responses and is linked to pulmonary alveolar proteinosis with hypogammaglobulinemia. Here, Magg et al. identified four heterozygous OAS1 gain-of-function mutations that cause a polymorphic immunodeficiency in six patients. The OAS1 mutants induced functional and transcriptomic alterations in monocytes, B cells, and T cells, which related to RNase L–dependent cellular dysfunction, apoptosis, protein translation arrest, and cellular RNA degradation. These deficiencies correlated to the altered structure of the OAS1 mutants. Some of these OAS1 gain-of-function patients were cured by hematopoietic stem cell transplantation, suggesting that these immune defects directly contributed to the disease phenotypes. These data give further insight into a rare autoinflammatory immunodeficiency.

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