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SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression.
Russell, Amanda J; Gray, Paul E; Ziegler, John B; Kim, Yae Jean; Smith, Sandy; Sewell, William A; Goodnow, Christopher C.
Afiliación
  • Russell AJ; Immunogenomics Laboratory, Garvan Institute of Medical Research, Darlinghurst, NSW 2010 Australia.
  • Gray PE; Sydney Children's Hospital, Randwick, NSW 2031, Australia.
  • Ziegler JB; School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2010, Australia.
  • Kim YJ; Sydney Children's Hospital, Randwick, NSW 2031, Australia.
  • Smith S; School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2010, Australia.
  • Sewell WA; Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
  • Goodnow CC; SydPath, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia.
Proc Natl Acad Sci U S A ; 118(34)2021 08 24.
Article en En | MEDLINE | ID: mdl-34417303
Sterile α motif domain-containing protein 9-like (SAMD9L) is encoded by a hallmark interferon-induced gene with a role in controlling virus replication that is not well understood. Here, we analyze SAMD9L function from the perspective of human mutations causing neonatal-onset severe autoinflammatory disease. Whole-genome sequencing of two children with leukocytoclastic panniculitis, basal ganglia calcifications, raised blood inflammatory markers, neutrophilia, anemia, thrombocytopaenia, and almost no B cells revealed heterozygous de novo SAMD9L mutations, p.Asn885Thrfs*6 and p.Lys878Serfs*13. These frameshift mutations truncate the SAMD9L protein within a domain a region of homology to the nucleotide-binding and oligomerization domain (NOD) of APAF1, ∼80 amino acids C-terminal to the Walker B motif. Single-cell analysis of human cells expressing green fluorescent protein (GFP)-SAMD9L fusion proteins revealed that enforced expression of wild-type SAMD9L repressed translation of red fluorescent protein messenger RNA and globally repressed endogenous protein translation, cell autonomously and in proportion to the level of GFP-SAMD9L in each cell. The children's truncating mutations dramatically exaggerated translational repression even at low levels of GFP-SAMD9L per cell, as did a missense Arg986Cys mutation reported recurrently as causing ataxia pancytopenia syndrome. Autoinflammatory disease associated with SAMD9L truncating mutations appears to result from an interferon-induced translational repressor whose activity goes unchecked by the loss of C-terminal domains that may normally sense virus infection.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pancitopenia / Ataxia / Biosíntesis de Proteínas / Síndromes Mielodisplásicos / Regulación de la Expresión Génica / Mutación Missense / Proteínas Supresoras de Tumor Límite: Child / Female / Humans / Male / Newborn Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pancitopenia / Ataxia / Biosíntesis de Proteínas / Síndromes Mielodisplásicos / Regulación de la Expresión Génica / Mutación Missense / Proteínas Supresoras de Tumor Límite: Child / Female / Humans / Male / Newborn Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos