Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia Kazutoshi Cho, Masafumi Yamada, Kazunaga.

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Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia Kazutoshi Cho, Masafumi Yamada, Kazunaga Agematsu, Hirokazu Kanegane, Noriko Miyake, Masahiro Ueki, Takuma Akimoto, Norimoto Kobayashi, Satoru Ikemoto, Mishie Tanino, Atsushi Fujita, Itaru Hayasaka, Satoshi Miyamoto, Mari Tanaka-Kubota, Koh Nakata, Masaaki Shiina, Kazuhiro Ogata, Hisanori Minakami, Naomichi Matsumoto, Tadashi Ariga The American Journal of Human Genetics Volume 102, Issue 3, Pages 480-486 (March 2018) DOI: 10.1016/j.ajhg.2018.01.019 Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 1 OAS1 Variants in Three Families with PAP and Evolutionary Conservation and Variations in OAS1 (A–C) Genetic analysis for OAS1 variation. Sanger sequencing demonstrated variations of (A) c.227C>T (p.Ala76Val) in family A, (B) c.326G>A (p.Cys109Tyr) in family B, and (C) c.592C>G (p.Leu198Val) in family C. Black arrows show the positions of the variations. (D) Schematic representation of OAS1 mutations. Black circles indicate the variants identified in this study. Blue and red triangles indicate metal binding sites (Asp75, Asp77, and Asp148) and ATP binding sites (Ser63, Lys213, and Gln229), respectively. Green and yellow boxes show the nucleotidyltransferase (NTP_transf_2) domain and 2′,5′-oligoadenylate synthetase 1, domain 2, and C terminus (OAS1_C) domain, respectively, predicted using the SMART program (see Web Resources). (E) Evolutionary conservation of Ala76, Cys109, and Leu198 amino acids in human OAS1. These amino acids are highlighted in green. Six orthologous sequences were aligned using the multiple sequence alignment program, Clustal Omega (see Web Resources). The American Journal of Human Genetics 2018 102, 480-486DOI: (10.1016/j.ajhg.2018.01.019) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 2 Impact of the Identified Variants on Protein Structure (A) Mapping of the mutations on the crystal structures of a double-stranded RNA (dsRNA)-bound form of human oligoadenylate synthetase 1 (hOAS1) and an apo form of porcine OAS1 (pOAS1) (PDB: 4ig8 and 1px5, respectively). The superimposed structures of the dsRNA-bound (cyan) and apo (green) forms of OAS1 are presented as ribbon diagrams. The stick model is shown in gray. The altered residues are shown as van der Waals spheres in blue and dark green in the dsRNA-bound and apo forms, respectively. The substrate analog, 2′-deoxy ATP (dATP), and magnesium ions are shown as orange sticks and purple balls, respectively. Close-up views around the mutation sites are shown separately for the dsRNA-bound and apo forms. In the close-up views, some side chains of the hydrophobic residues around the mutation sites are shown as translucent spheres. (B) The free energy changes associated with each variant in a dsRNA-bound form of hOAS1 and apo form of pOAS1 by the FoldX software are shown. The American Journal of Human Genetics 2018 102, 480-486DOI: (10.1016/j.ajhg.2018.01.019) Copyright © 2018 American Society of Human Genetics Terms and Conditions