ArticleBlood2007
Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis.
Article in Blood, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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Who cites it
90 citing papers in PubMed, 204 citations in OpenAlex.
- Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells.The Journal of clinical investigation · 2015Trial
- Genetic influences on haematopoiesis.Nature reviews. Genetics · 2026Review
- CRISPR-based therapeutic genome editing for inherited blood disorders.Nature reviews. Drug discovery · 2025Review
- Review
- Diagnosis and management of neutropenia.Blood research · 2025Review
- A new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations.Blood · 2025Article
- Extended clinical phenotypes and treatment modalities in 32 JAGN1-deficient patients: a multicenter study by ESID and EBMT IEWP.Blood advances · 2025Article
- Contribution of next generation sequencing to the diagnosis of inborn errors of immunity in a pediatric cohort.Frontiers in immunology · 2025Article
- Cyclic neutropenia: a case report and literature review.American journal of translational research · 2025Article
- De Novo Deep Intron ELANE Mutation Resulting in Severe Congenital Neutropenia.Journal of clinical immunology · 2024Article
- A JAGN1-associated severe congenital neutropenia zebrafish model revealed an altered G-CSFR signaling and UPR activation.Blood advances · 2024Article
- CRISPR-Cas9n-mediated ELANE promoter editing for gene therapy of severe congenital neutropenia.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Clinical Characteristics and Treatment Response of a Novel ELANE Gene Mutation (c.295_303del) in Congenital Neutropenia.Mediterranean journal of hematology and infectious diseases · 2024Article
- Article
- Mutant allele knockout with novel CRISPR nuclease promotes myelopoiesis in ELANE neutropenia.Molecular therapy. Methods & clinical development · 2022Article
- Lymphocyte cytosolic protein 1 (L-plastin) I232F mutation impairs granulocytic proliferation and causes neutropenia.Blood advances · 2022Article
- Article
- Case Report: Association between cyclic neutropenia and SRP54 deficiency.Frontiers in immunology · 2022Article
- Dissecting ELANE neutropenia pathogenicity by human HSC gene editing.Cell stem cell · 2021Article
- Identification of biallelic germline variants of SRP68 in a sporadic case with severe congenital neutropenia.Haematologica · 2021Article
30 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Mutations of the ELA2 gene encoding neutrophil elastase (NE) are responsible for most cases of SCN and cyclic neutropenia (CN), a related but milder disorder of granulopoiesis. However, the mechanisms by which these mutations disrupt granulopoiesis are unclear. We hypothesize that the ELA2 mutations result in the production of misfolded NE protein, activation of the unfolded protein response (UPR), and ultimately apoptosis of granulocytic precursors. Expression of mutant NE but not wild-type NE strongly induced BiP/GRP78 mRNA expression and XBP1 mRNA splicing, 2 classic markers of the UPR. The magnitude of UPR activation by a specific ELA2 mutation correlated with its associated clinical phenotype. Consistent with the UPR model, expression of mutant NE in primary human granulocytic precursors increased expression of CHOP (DDITS) and induced apoptosis in a protease-independent fashion. Most strikingly, UPR activation and decreased NE protein expression were detected in primary granulocytic precursors from SCN patients. Collectively, these data provide strong support for a UPR model of SCN disease pathogenesis and place SCN in a growing list of human diseases caused by misfolded proteins.
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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.