Infantile-onset primary alveolar proteinosis with hypogammaglobulinemia caused by heterozygous mutations of 2′-5′-oligoadenylate synthase 1

Abstract

Abstract 2′-5′-oligoadenylate synthase 1 (OAS1) is one of the interferon-stimulated genes (ISG) which plays a critical role in innate anti-viral immunity. Stimulated by viral double strand RNA (dsRNA), OAS1 produces 2′-5′ linked oligomer of adenylates (2′-5′A) and the produced 2′-5′A activates ribonuclease-L (RNase-L) which results in degradation of viral RNA and inhibition of viral replications. We identified autosomal inherited OAS1 missense mutations in three Japanese pedigrees with infantile-onset primary alveolar proteinosis with hypogammaglobulinemia. Patients’ peripheral blood monocytes and CD11c+ myeloid dendritic cells (mDC) were progressively decreased; CD27+ memory B cells were lacking. The alveolar macrophages showed decreased phagocytosis activity; and the enlarged and foamy form was scarcely observed, which were typical in conventional pulmonary alveolar proteinosis (PAP). Their bone marrow monocyte progenitors were decreased and showed reduced colony forming potentials. One of the patients is currently alive without PAP after hematopoietic stem cell transplantation. The recombinant mutant OAS1 protein had unaltered dsRNA binding activity. Patient-derived lymphoblastoid cell lines showed normal expression of OAS1 protein and mRNA, and unaltered function in OAS1 - RNase-L pathway. We generated model OAS1 knock-in mice by CRISPR/Cas9 based gene editing and analyzed immune-phenotypes. The mice show normal B and DC numbers and normal serum immunoglobulin levels so far. Detailed functional study on mutant OAS1 protein with the multi-Omics approach is currently underway.