SAMD9L autoinflammatory or ataxia pancytopenia disease mutations activate cell-autonomous translational repression

Abstract

Significance The experiments here advance understanding of the function of the SAMD9L gene and protein in innate immune mechanisms in resisting virus infection and in the pathogenesis of inflammatory, hematological, and neurological disorders. The clinical syndrome defined in two children with de novo truncating SAMD9L mutations expands the phenotypes in this newly recognized autoinflammatory disorder. Analysis of cells expressing normal or mutant SAMD9L reveals the protein represses protein translation, with the truncating mutations greatly exaggerating this activity. The experiments find equally potent gain of function caused by the truncating mutations or a recurrent missense mutation associated with clinically milder ataxia and pancytopenia syndromes, demonstrating that diverse clinical manifestations can arise from mutations that appear cell-biologically equivalent.

Progression of non‐hematologic manifestations in SAMD9L‐associated autoinflammatory disease (SAAD) after hematopoietic stem cell transplantation

“…Whole-exome sequencing analysis of the patient revealed the SAAD-associated de novo c.2658-2659del, p.F886Lfs*11 mutation of SAMD9L gene, confirmed by Sanger sequencing. 3,5 The present case highlights the benefit of early HSCT in SAAD, as reported in the literature (Table S2), 3,[5][6][7] showing its limits on extra-hematological manifestations. The absence of acute graftversus-host disease and the low acute toxicity displayed by our patient after alpha/beta/CD19-depleted haplo-HSCT may suggest this approach as a valid therapeutic strategy.…”

“…The present case highlights the benefit of early HSCT in SAAD, as reported in the literature (Table ), 3,5–7 showing its limits on extra‐hematological manifestations. The absence of acute graft‐versus‐host disease and the low acute toxicity displayed by our patient after alpha/beta/CD19‐depleted haplo‐HSCT may suggest this approach as a valid therapeutic strategy.…”

Mutant Samd9l expression impairs hematopoiesis and induces bone marrow failure in mice

“…Together, our data demonstrated that inflammation potentiates Samd9l-Mut phenotypes, in particular, pancytopenia with lymphopenia, corresponding to clinical observations in patients with SAMD9L mutations (13,(29)(30)(31).…”

“…They are interferon-responsive genes, and their expression dramatically increases following exposure to interferons (IFN) and TNFα (10)(11)(12). In addition to the germline mutations observed in patients with BMF and myeloid neoplasms, SAMD9L mutations have also been associated with inflammatory diseases (13).…”

When extended genetics rescues diagnosis: a patient with CANDLE-like phenotype and de novo mutation in theSAMD9Lgene

“…SAMD9L-SAAD is a new entity previously described in eight patients whose clinical features overlap with CANDLE4 5 (see online supplemental file 1). The overall phenotype of patients is very severe as three out of eight patients deceased at an early age and three other one of them underwent bone marrow transplantation for severe cytopenia or intersticial lung disease (ILD).…”