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.
Germline SAMD9L truncation variants trigger global translational repression
Disclosures: J. Debley reported grants from NIH/NIAID during the conduct of the study and grants from NIH/NIAID outside the submitted work. No other disclosures were reported.
- Views Icon Views
- Share Icon Share
- Search Site
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; Germline SAMD9L truncation variants trigger global translational repression. J Exp Med 3 May 2021; 218 (5): e20201195. doi: https://doi.org/10.1084/jem.20201195
Download citation file: