Heterozygous OAS1 Gain-of-Function Variants Cause a Polymorphic Autoinflammatory and Immunodeficiency Syndrome

Oligoadenylate synthase 1 (OAS1) is a type-1 interferon-inducible, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate (2-5A) to activate RNaseL as a means of antiviral defense. We report four de novo heterozygous OAS1 variants in five patients. Variant OAS1 proteins show dsRNA-independent gain-of-function 2-5A synthetase activity that results in RNaseL-mediated RNA-cleavage, transcriptomic downregulation, and functional impairment and/or apoptosis of monocytes, iPSC-derived macrophages, and B-cells. This leads to a polymorphic syndrome of monocyte, macrophage, and B-cell deficiency characterized by autoinflammation, pulmonary alveolar proteinosis, and hypogammaglobulinemia. RNase-L-inhibition in vitro mitigates, and hematopoietic cell transplantation in vivo corrects the autoinflammatory and immunodeficiency phenotype. iPSC-derived macrophages, poly-A tailed mRNA isolation, library preparation and quantification were performed with NEBNext kits (New England Biolabs, Ipswich, USA) following manufacture’s instructions. Libraries were sequenced on a NextSeq 500 (Illumina, San Diego, USA) Poly-A selection?based RNA sequencing (RNA-seq) was performed on FACS-sorted OAS1-WT (three different healthy donors (HD), HD1 and HD2 in duplicates) and A76V (in duplicates) CD14 monocytes, CD19 B cells, and CD3 T cells. Libraries were sequenced on a single lane in 100 bp single end mode on a HiSeq1500 instrument (Illumina, San Diego, USA).