Neutrophil Elastase Defects in Congenital Neutropenia

Rydzynska, Zuzanna; Pawlik, Bartłomiej; Krzyżanowski, Damian; Młynarski, Wojciech; Madzio, Joanna

doi:10.3389/fimmu.2021.653932

Cited by 28 publications

(55 citation statements)

References 114 publications

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“…Applying WES, all patients were harboring heterozygous mutations in the ELANE gene. Most mutations were located in exon 3, were associated with variable phenotypes, and might be a life-threatening condition (Rydzynska et al, 2021); moreover, SCN due to ELANE mutations cause neutropenia starting at birth like in patient 1 and patient 3. Meanwhile, patient 2 had a late onset disease than others because the disease phenotype is not determined by mutation alone; it can be influenced by different genetic, epigenetic, and environmental levels (Makaryan et al, 2015;Nayak et al, 2015;Nustede et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

De novo mutations of \(\textit{ ELANE}\) gene in three Vietnamese patients with severe congenital neutropenia

Linh

Anh

Tung

et al. 2022

AJB

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Severe congenital neutropenia (SCN) is a congenital condition in which granulocytes mature abnormally owing to a variety of genetic defects, resulting in immunodeficiency. Among the several genetic variations related to SCN, heterozygous mutations in the ELANE gene encoding neutrophil elastase account for approximately 60% of the genetic causes. Here, we present three patients from different Vietnamese families who were susceptible to infectious diseases such as lung abscesses, sepsis, cellulitis, and septicemia. Moreover, their hematological and immunological parameters were below the reference range. Whole exome sequencing (WES) analysis was performed in all cases harboring three previously described disease-causing mutations, including p.Arg103Pro, p.Trp156Arg, and p.Arg81Pro in the ELANE gene (NM_001972.4). These mutations were confirmed by the Sanger sequencing method in the patients, helping to identify de novo mutations in all cases. Our data increase more evidence for the function of ELANE in SCN, as well as raise awareness of this rare disease in the context of frequent infections in Vietnam.

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Section: Discussionmentioning

confidence: 99%

De novo mutations of \(\textit{ ELANE}\) gene in three Vietnamese patients with severe congenital neutropenia

Linh

Anh

Tung

et al. 2022

AJB

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“…Furthermore, granulopoiesis and nuclei segmentation occur in parallel. It has been observed that many mutations in the gene for the primary granule protein neutrophil elastase (ELANE) cause neutropenia [38]. There are currently several hypotheses on the mechanism involved, most related to misfolded protein.…”

Section: Transcription and Nuclei Structure Intertwinementioning

confidence: 99%

Current Understanding of the Neutrophil Transcriptome in Health and Disease

Garratt

2021

Cells

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Neutrophils are key cells of the innate immune system. It is now understood that this leukocyte population is diverse in both the basal composition and functional plasticity. Underlying this plasticity is a post-translational framework for rapidly achieving early activation states, but also a transcriptional capacity that is becoming increasingly recognized by immunologists. Growing interest in the contribution of neutrophils to health and disease has resulted in more efforts to describe their transcriptional activity. Whilst initial efforts focused predominantly on understanding the existing biology, investigations with advanced methods such as single cell RNA sequencing to understand interactions of the entire immune system are revealing higher flexibility in neutrophil transcription than previously thought possible and multiple transition states. It is now apparent that neutrophils utilise many forms of RNA in the regulation of their function. This review collates current knowledge on the nuclei structure and gene expression activity of human neutrophils across homeostasis and disease, before highlighting knowledge gaps that are research priority areas.

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“…Both conditions are treated effectively now with recombinant human granulocyte colony-stimulating factor (G-CSF), but this treatment requires daily or alternate day subcutaneous injections and carries the potential risk of stimulating development of myeloid leukemia. Currently hematopoietic stem cell transplantation is the only other effective treatment; thus, there is a need for alternative therapies [1][2][3][4][5][6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Comparison of Gene Editing versus a Neutrophil Elastase Inhibitor as Potential Therapies for ELANE Neutropenia

Makaryan

Kelley

Fletcher

et al. 2022

Journal of Cellular Immunology

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Heterozygous mutations in ELANE , the gene for neutrophil elastase, cause cyclic and congenital neutropenia through the programed cell death of neutrophil progenitors in the bone marrow. Granulocyte colony-stimulating factor is an effective therapy for these diseases, but alternative therapies are needed, especially for patients who do not respond well or are at high risk of developing myeloid malignancies. We developed an HL60 cell model for ELANE neutropenia and previously demonstrated that transient and regulated expression of mutant ELANE causes cell death by accelerated apoptosis. Knocking down the mutant gene or exposure to a potent inhibitor of neutrophil elastase rescued neutrophil development. Because of the great diversity in causative ELANE mutations, we generated stable HL60 clones expressing mutant P139L, C151Y and G214R and compared the effects of elastase inhibitor exposure to an ELANE knock-out line on cell development and function. ATRA induced differentiation demonstrated comparably impaired myeloid cell development for all three lines with upregulated expression of GRP78/BIP, an abnormality corrected by exposure of these cells to the elastase inhibitor MK-0339. The inhibitor and KO of mutant ELANE led to formation of neutrophils with comparable chemotactic and bactericidal capacities. We concluded that both strategies have great potential for the treatment of cyclic and congenital neutropenia. However, an orally absorbed, cell permeable inhibitor of neutrophil elastase, if proven safe and effective in a clinical trial, might be the better alternative to G-CSF or gene editing to treat ELANE neutropenia.

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Neutrophil Elastase Defects in Congenital Neutropenia

Cited by 28 publications

References 114 publications

De novo mutations of \(\textit{ ELANE}\) gene in three Vietnamese patients with severe congenital neutropenia

De novo mutations of \(\textit{ ELANE}\) gene in three Vietnamese patients with severe congenital neutropenia

Current Understanding of the Neutrophil Transcriptome in Health and Disease

Comparison of Gene Editing versus a Neutrophil Elastase Inhibitor as Potential Therapies for ELANE Neutropenia

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