ArticleBlood2014
Neutropenia-associated ELANE mutations disrupting translation initiation produce novel neutrophil elastase isoforms.
Article in Blood, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 49 citations in OpenAlex.
- Neutrophil function in children following allogeneic hematopoietic stem cell transplant.Pediatric transplantation · 2016Trial
- Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells.The Journal of clinical investigation · 2015Trial
- Innate immunity: current understandings and future perspectives.Signal transduction and targeted therapy · 2026Review
- Review
- Genome-wide detection of human 5' UTR variants that impact protein translation.American journal of human genetics · 2026Article
- De Novo Missense Variant c.170 C > A of ELANE in a Chinese Infant with Congenital Neutropenia: Case Report and Literature Review.Journal of clinical immunology · 2025Review
- Cyclic neutropenia: a case report and literature review.American journal of translational research · 2025Article
- G-CSF resistance of ELANE-mutant neutropenia depends on SERF1-containing truncated-neutrophil elastase aggregates.The Journal of clinical investigation · 2024Article
- De Novo Deep Intron ELANE Mutation Resulting in Severe Congenital Neutropenia.Journal of clinical immunology · 2024Article
- 'Off the shelf' immunotherapies: Generation and application of pluripotent stem cell-derived immune cells.Cell proliferation · 2023Review
- CD63 acts as a functional marker in maintaining hematopoietic stem cell quiescence through supporting TGFβ signaling in mice.Cell death and differentiation · 2022Article
- Review
- Article
- Dissecting ELANE neutropenia pathogenicity by human HSC gene editing.Cell stem cell · 2021Article
- Neutrophil Elastase Defects in Congenital Neutropenia.Frontiers in immunology · 2021Review
- Getting Back to Normal: Correcting SCN by Universal or Precision Strikes.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- Article
- NovelJournal of pediatric genetics · 2020Article
- CRISPR/Cas9-mediatedHaematologica · 2020Article
- Cathepsin G Inhibition by Serpinb1 and Serpinb6 Prevents Programmed Necrosis in Neutrophils and Monocytes and Reduces GSDMD-Driven Inflammation.Cell reports · 2019Article
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Authors and funding
13 authors at 6 institutions in 2 countries.
Funding
Abstract
Hereditary neutropenia is usually caused by heterozygous germline mutations in the ELANE gene encoding neutrophil elastase (NE). How mutations cause disease remains uncertain, but two hypotheses have been proposed. In one, ELANE mutations lead to mislocalization of NE. In the other, ELANE mutations disturb protein folding, inducing an unfolded protein response in the endoplasmic reticulum (ER). In this study, we describe new types of mutations that disrupt the translational start site. At first glance, they should block translation and are incompatible with either the mislocalization or misfolding hypotheses, which require mutant protein for pathogenicity. We find that start-site mutations, instead, force translation from downstream in-frame initiation codons, yielding amino-terminally truncated isoforms lacking ER-localizing (pre) and zymogen-maintaining (pro) sequences, yet retain essential catalytic residues. Patient-derived induced pluripotent stem cells recapitulate hematopoietic and molecular phenotypes. Expression of the amino-terminally deleted isoforms in vitro reduces myeloid cell clonogenic capacity. We define an internal ribosome entry site (IRES) within ELANE and demonstrate that adjacent mutations modulate IRES activity, independently of protein-coding sequence alterations. Some ELANE mutations, therefore, appear to cause neutropenia via the production of amino-terminally deleted NE isoforms rather than by altering the coding sequence of the full-length protein.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.