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

Sci Immunol. 2021 Jun 18;6(60):eabf9564. doi: 10.1126/sciimmunol.abf9564.


Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon-induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell-derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L-mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2',5'-Oligoadenylate Synthetase / genetics*
  • 2',5'-Oligoadenylate Synthetase / immunology
  • 2',5'-Oligoadenylate Synthetase / isolation & purification
  • 2',5'-Oligoadenylate Synthetase / metabolism
  • B-Lymphocytes / immunology
  • Cells, Cultured
  • DNA Mutational Analysis
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Enzyme Assays
  • Gain of Function Mutation / immunology
  • Gene Knockout Techniques
  • Hematopoietic Stem Cell Transplantation
  • Hereditary Autoinflammatory Diseases / diagnosis
  • Hereditary Autoinflammatory Diseases / genetics*
  • Hereditary Autoinflammatory Diseases / immunology
  • Hereditary Autoinflammatory Diseases / therapy
  • Heterozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Interferon Type I / metabolism
  • Macrophages / immunology
  • Molecular Dynamics Simulation
  • Monocytes / immunology
  • Primary Cell Culture
  • Primary Immunodeficiency Diseases / diagnosis
  • Primary Immunodeficiency Diseases / genetics*
  • Primary Immunodeficiency Diseases / immunology
  • Primary Immunodeficiency Diseases / therapy
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology


  • Interferon Type I
  • Recombinant Proteins
  • OAS1 protein, human
  • 2',5'-Oligoadenylate Synthetase
  • Endoribonucleases
  • 2-5A-dependent ribonuclease