@article {1011, title = {Germline SAMD9L truncation variants trigger global translational repression.}, journal = {J Exp Med}, volume = {218}, year = {2021}, month = {2021 May 03}, abstract = {

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.

}, issn = {1540-9538}, doi = {10.1084/jem.20201195}, author = {Allenspach, Eric J and Soveg, Frank and Finn, Laura S and So, Lomon and Gorman, Jacquelyn A and Rosen, Aaron B I and Skoda-Smith, Suzanne and Wheeler, Marsha M and Barrow, Kaitlyn A and Rich, Lucille M and Debley, Jason S and Bamshad, Michael J and Nickerson, Deborah A and Savan, Ram and Torgerson, Troy R and Rawlings, David J} } @article {502, title = { and Mutations Implicate RAB5 Regulation in Nephrotic Syndrome.}, journal = {J Am Soc Nephrol}, volume = {29}, year = {2018}, month = {2018 Aug}, pages = {2123-2138}, abstract = {

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of CKD. The discovery of monogenic causes of SRNS has revealed specific pathogenetic pathways, but these monogenic causes do not explain all cases of SRNS.

METHODS: To identify novel monogenic causes of SRNS, we screened 665 patients by whole-exome sequencing. We then evaluated the functional significance of two genes and the mutations therein that we discovered through this sequencing and conducted complementary studies in podocyte-like nephrocytes.

RESULTS: We identified conserved, homozygous missense mutations of in two families with early-onset NS and a homozygous missense mutation of in two siblings with SRNS. GAPVD1 and ANKFY1 interact with the endosomal regulator RAB5. Coimmunoprecipitation assays indicated interaction between GAPVD1 and ANKFY1 proteins, which also colocalized when expressed in HEK293T cells. Silencing either protein diminished the podocyte migration rate. Compared with wild-type GAPVD1 and ANKFY1, the mutated proteins produced upon ectopic expression of or bearing the patient-derived mutations exhibited altered binding affinity for active RAB5 and reduced ability to rescue the knockout-induced defect in podocyte migration. Coimmunoprecipitation assays further demonstrated a physical interaction between nephrin and GAPVD1, and immunofluorescence revealed partial colocalization of these proteins in rat glomeruli. The patient-derived mutations reduced nephrin-GAPVD1 binding affinity. In , silencing impaired endocytosis and caused mistrafficking of the nephrin ortholog.

CONCLUSIONS: Mutations in and probably in are novel monogenic causes of NS. The discovery of these genes implicates RAB5 regulation in the pathogenesis of human NS.

}, issn = {1533-3450}, doi = {10.1681/ASN.2017121312}, author = {Hermle, Tobias and Schneider, Ronen and Schapiro, David and Braun, Daniela A and van der Ven, Amelie T and Warejko, Jillian K and Daga, Ankana and Widmeier, Eugen and Nakayama, Makiko and Jobst-Schwan, Tilman and Majmundar, Amar J and Ashraf, Shazia and Rao, Jia and Finn, Laura S and Tasic, Velibor and Hernandez, Joel D and Bagga, Arvind and Jalalah, Sawsan M and El Desoky, Sherif and Kari, Jameela A and Laricchia, Kristen M and Lek, Monkol and Rehm, Heidi L and MacArthur, Daniel G and Mane, Shrikant and Lifton, Richard P and Shril, Shirlee and Hildebrandt, Friedhelm} }