SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression.
Proc Natl Acad Sci U S A
; 118(34)2021 08 24.
Article
en En
| MEDLINE
| ID: mdl-34417303
ABSTRACT
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, â¼80 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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1
Bases de datos:
MEDLINE
Asunto principal:
Pancitopenia
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Ataxia
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Biosíntesis de Proteínas
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Síndromes Mielodisplásicos
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Regulación de la Expresión Génica
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Mutación Missense
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Proteínas Supresoras de Tumor
Límite:
Child
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Female
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Humans
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Male
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Newborn
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2021
Tipo del documento:
Article