Details

Autor(en) / Beteiligte

• Allenspach, Eric J
• Soveg, Frank
• Finn, Laura S
• So, Lomon
• Gorman, Jacquelyn A
• Rosen, Aaron B I
• Skoda-Smith, Suzanne
• Wheeler, Marsha M
• Barrow, Kaitlyn A
• Rich, Lucille M
• Debley, Jason S
• Bamshad, Michael J
• Nickerson, Deborah A
• Savan, Ram
• Torgerson, Troy R
• Rawlings, David J

Titel

Germline SAMD9L truncation variants trigger global translational repression

Ist Teil von

• The Journal of experimental medicine, 2021-05, Vol.218 (5)

Ort / Verlag

United States: Rockefeller University Press

Erscheinungsjahr

2021

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.