Heterozygous <i>OAS1</i> gain-of-function variants cause an autoinflammatory immunodeficiency
Thomas Magg, Tsubasa Okano, Lars M. Koenig, Daniel F. R. Boehmer, Samantha L. Schwartz, Kento Inoue, Jennifer Heimall, Francesco Licciardi, Julia Ley‐Zaporozhan, Ronald M. Ferdman, Andrés Caballero-Oteyza, Esther N Park, Brenda M. Calderon, Debayan Dey, Hirokazu Kanegane, Kazutoshi Cho, Davide Montin, Karl Reiter, Matthias Griese, Michael H. Albert, Meino Rohlfs, Paul Gray, Christoph Walz, Graeme L. Conn, Kathleen E. Sullivan, Christoph Klein, Tomohiro Morio, Fabian Hauck
Abstract
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.