The genetic, molecular, and cellular analysis of autoinflammatory and immunodeficiency disorders contributes to our understanding of human immunity and leads to the development of targeted therapies. Oligoadenylate synthase 1 (OAS1) is an intracellular double-stranded RNA sensor that generates the second messenger 2'-5'-oligoadenylate to activate RNaseL as a means of antiviral defense. We analyzed four unrelated patients with a polymorphic syndrome of fever, dermatitis, pulmonary alveolar proteinosis, inflammatory bowel disease, and hypogammaglobulinemia.
We performed exome and transcriptome sequencing, RNA and protein biochemistry, heterologous and autologous molecular and cellular functional analyses, cellular and serologic immune phenotyping, and allogeneic hematopoietic stem cell transplantation.
We found three de novoheterozygous OAS1variants in four unrelated patients. Variant OAS1 proteins showed double-stranded RNA-independent increased in vitro enzyme activity. They constitutively activated RNaseL resulting in increased RNA cleavage in a heterologous cell system as well as in primary monocytes and B cells. This lead to an increased interferon response, spontaneous monocyte and B cell apoptosis, impaired monocyte and B cell differentiation and function, and impaired cellular co-stimulation towards T cells. Allogeneic hematopoietic stem cell transplantation corrected the otherwise lethal phenotype.
Heterozygous OAS1 gain-of-function variants cause a polymorphic autoinflammatory and immunodeficiency syndrome that can be cured by allogeneic hematopoietic stem cell transplantation. OAS1 emerges as a critical regulator of monocyte and B cell human biology.