SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 118; no. 34; pp. 1 - 11
Main Authors Russell, Amanda J., Gray, Paul E., Ziegler, John B., Kim, Yae Jean, Smith, Sandy, Sewell, William A., Goodnow, Christopher C.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 24.08.2021
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Summary: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 ofwild-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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Reviewers: A.F., Institut Imagine des Maladies Génétiques; and B.M., National Institute of Allergy and Infectious Diseases, NIH.
Contributed by Christopher C. Goodnow, July 11, 2021 (sent for review June 16, 2021; reviewed by Alain Fischer and Bernard Moss)
Author contributions: A.J.R., P.E.G., and C.C.G. designed research; A.J.R., P.E.G., J.B.Z., Y.J.K., S.S., and W.A.S. performed research; A.J.R., P.E.G., J.B.Z., Y.J.K., S.S., W.A.S., and C.C.G. analyzed data; and A.J.R., P.E.G., and C.C.G. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2110190118