@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 {946, title = {Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares.}, journal = {Pediatr Rheumatol Online J}, volume = {18}, year = {2020}, month = {2020 Oct 16}, pages = {80}, abstract = {

BACKGROUND: Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited.

CASE PRESENTATION: We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264_269delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636 + 2 T > A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells.

CONCLUSIONS: Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.

}, issn = {1546-0096}, doi = {10.1186/s12969-020-00474-1}, author = {Chau, Alice S and Cole, Bonnie L and Debley, Jason S and Nanda, Kabita and Rosen, Aaron B I and Bamshad, Michael J and Nickerson, Deborah A and Torgerson, Troy R and Allenspach, Eric J} }