• Germline SAMD9L truncation variants trigger global translational repression.

Germline SAMD9L truncation variants trigger global translational repression.

The Journal of experimental medicine (2021-03-17)
Eric J Allenspach, Frank Soveg, Laura S Finn, Lomon So, Jacquelyn A Gorman, Aaron B I Rosen, Suzanne Skoda-Smith, Marsha M Wheeler, Kaitlyn A Barrow, Lucille M Rich, Jason S Debley, Michael J Bamshad, Deborah A Nickerson, Ram Savan, Troy R Torgerson, David J Rawlings

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.

Product Number
Product Description

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