Germline SAMD9L truncation variants trigger global translational repression.

TitleGermline SAMD9L truncation variants trigger global translational repression.
Publication TypeJournal Article
Year of Publication2021
AuthorsAllenspach, EJ, Soveg, F, Finn, LS, So, L, Gorman, JA, Rosen, ABI, Skoda-Smith, S, Wheeler, MM, Barrow, KA, Rich, LM, Debley, JS, Bamshad, MJ, Nickerson, DA, Savan, R, Torgerson, TR, Rawlings, DJ
JournalJ Exp Med
Date Published2021 May 03

SAMD9L is an interferon-induced tumor suppressor implicated in a spectrum of multisystem disorders, including risk for myeloid malignancies and immune deficiency. We identified a heterozygous de novo frameshift variant in SAMD9L in an infant with B cell aplasia and clinical autoinflammatory features who died from respiratory failure with chronic rhinovirus infection. Autopsy demonstrated absent bone marrow and peripheral B cells as well as selective loss of Langerhans and Purkinje cells. The frameshift variant led to expression of a truncated protein with interferon treatment. This protein exhibited a gain-of-function phenotype, resulting in interference in global protein synthesis via inhibition of translational elongation. Using a mutational scan, we identified a region within SAMD9L where stop-gain variants trigger a similar translational arrest. SAMD9L variants that globally suppress translation had no effect or increased mRNA transcription. The complex-reported phenotype likely reflects lineage-dominant sensitivities to this translation block. Taken together, our findings indicate that interferon-triggered SAMD9L gain-of-function variants globally suppress translation.

Alternate JournalJ Exp Med
PubMed ID33724365
PubMed Central IDPMC7970252
Grant ListUM1 HG006493 / HG / NHGRI NIH HHS / United States