Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.37 (neutrophil elastase)
4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe congenital neutropenia (SCN) is characterized by neutropenia, recurrent bacterial infections, and maturation arrest in the bone marrow. Although many cases have mutations in the ELA2 gene encoding neutrophil elastase, a significant proportion remain undefined at a molecular level. A mutation (Leu270Pro) in the gene encoding the Wiskott-Aldrich syndrome protein (WASp) resulting in an X-linked SCN kindred has been reported. We therefore screened the WAS gene in 14 young SCN males with wild-type ELA2 and identified 2 with novel mutations, one who presented with myelodysplasia (Ile294Thr) and the other with classic SCN (Ser270Pro). Both patients had defects of immunologic function including a generalized reduction of lymphoid and natural killer cell numbers, reduced lymphocyte proliferation, and abrogated phagocyte activity. In vitro culture of bone marrow progenitors demonstrated a profound reduction in neutrophil production and increased levels of apoptosis, consistent with an intrinsic disturbance of normal myeloid differentiation as the cause of the neutropenia. Both mutations resulted in increased WASp activity and produced marked abnormalities of cytoskeletal structure and dynamics. Furthermore, these results also suggest a novel cause of myelodysplasia and that male children with myelodysplasia and disturbance of immunologic function should be screened for such mutations.
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PMID:Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia. 1680 17

Severe congenital neutropenia (CN) includes a variety of hematologic disorders characterized by severe neutropenia, with absolute neutrophil counts (ANC) below 0.5 x 10(9)/L, and associated with severe systemic bacterial infections from early infancy. One subtype of CN, Kostmann syndrome, is an autosomal recessive disorder, characterized histopathologically by early-stage maturation arrest of myeloid differentiation. CN with similar clinical features occurs as an autosomal dominant disorder and many sporadic cases also have been reported. This genetic heterogeneity suggests that several pathophysiological mechanisms may lead to this common clinical phenotype. Recent studies on the genetic bases of CN have detected inherited or spontaneous point mutations in the neutrophil elastase gene (ELA 2) in about 60% to 80% of patients and, less commonly, mutations in other genes. Acquisition of additional genetic defects during the course of the disease, for example, granulocyte colony-stimulating factor (G-CSF) receptor gene mutations and cytogenetic aberrations, indicates an underlying genetic instability as a common feature for all congenital neutropenia subtypes. Data on more than 600 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) demonstrate that, regardless of the particular CN subtype, more than 95% of these patients respond to recombinant human (rHu)G-CSF with ANCs that can be maintained above 1.0 x 10(9)/L. Adverse events include mild splenomegaly, osteoporosis, and malignant transformation into myelodysplasia (MDS)/leukemia. If and how G-CSF treatment impacts on these adverse events is not fully understood. In recent analyses the influence of the G-CSF dose required to achieve neutrophil response (ANC >1,000/microL) in the risk of developing acute myeloid leukemia (AML) has been reported. Hematopoietic stem cell transplantation (HSCT) is still the only treatment available for patients who are refractory to G-CSF treatment.
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PMID:Severe congenital neutropenia. 1682 61

Mutations in ELA2 encoding the neutrophil granule protease, neutrophil elastase (NE), are the major cause of the 2 main forms of hereditary neutropenia, cyclic neutropenia and severe congenital neutropenia (SCN). Genetic evaluation of other forms of neutropenia in humans and model organisms has helped to illuminate the role of NE. A canine form of cyclic neutropenia corresponds to human Hermansky-Pudlak syndrome type 2 (HPS2) and results from mutations in AP3B1 encoding a subunit of a complex involved in the subcellular trafficking of vesicular cargo proteins (among which NE appears to be one). Rare cases of SCN are attributable to mutations in the transcriptional repressor Gfi1 (among whose regulatory targets also include ELA2). The ultimate biochemical consequences of the mutations are not yet known, however. Gene targeting of ELA2 has thus far failed to recapitulate neutropenia in mice. The cycling phenomenon and origins of leukemic transformation in SCN remain puzzling. Nevertheless, mutations in all 3 genes are capable of causing the mislocalization of NE and may also induce the unfolded protein response, suggesting that there might a convergent pathogenic mechanism focusing on NE.
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PMID:Neutrophil elastase in cyclic and severe congenital neutropenia. 1705 55

Proteases and their serpin inhibitors are abundantly expressed in haemopoietic and peripheral blood cells. There is, however, relatively little information about the role played by serpins in the control of protease activity within these cells and in the pericellular region. The observation that mutations in the neutrophil elastase gene, which cause cyclic and severe congenital neutropenia, are associated with protease maldistribution gives some clue as to the potential importance of inhibitor proteins. To begin to address the role of protease/inhibitor balance in blood cells we used reverse transcription polymerase chain reaction to examine protease and serpin gene expression in mature peripheral blood cells, differentiating haemopoietic progenitors, leukaemic blasts and haemopoietic cell lines. The results demonstrate stage-specific expression of proteases together with widespread expression of intra- and extra-cellular serpins. The elastase inhibitors monocyte neutrophil elastase inhibitor (MNEI) and antitrypsin (AT) showed overlapping expression. MNEI is predominantly expressed in early haemopoietic progenitors while antitrypsin is mainly expressed in more mature myeloid precursors, peripheral blood granulocytes and mononuclear cells. Our results give an overall picture of serpin and protease gene expression and draws attention to the potential importance of elastase regulators at all stages of myelopoiesis.
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PMID:Stage specific gene expression of serpins and their cognate proteases during myeloid differentiation. 1710 53

Congenital neutropenia is a rare hematopoietic disease, which occurs sporadically or as an auto-somal dominant inherited disorder. Pathogenesis of congenital neutropenia can now be attributed to mutations of the ELA2 gene encoding neutrophil elastase. A child with severe congenital neutropenia with a heterozygous mutation G1887A in exon 2 of ELA2 gene is reported.
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PMID:Molecular screening of the neutrophil elastase gene in congenital neutropenia. 1720 6

Granule proteins play a major role in bacterial killing by neutrophils. Serglycin proteoglycan, the major intracellular proteoglycan of hematopoietic cells, has been proposed to play a role in sorting and packing of granule proteins. We examined the content of major neutrophil granule proteins in serglycin knockout mice and found neutrophil elastase absent from mature neutrophils as shown by activity assay, Western blotting, and immunocytochemistry, whereas neutrophil elastase mRNA was present. The localization of other neutrophil granule proteins did not differ between wild-type and serglycin knockout mice. Differential counts and neutrophil ultrastructure were unaffected by the lack of serglycin, indicating that defective localization of neutrophil elastase does not induce neutropenia itself, albeit mutations in the neutrophil elastase gene can cause severe congenital neutropenia or cyclic neutropenia. The virulence of intraperitoneally injected Gram-negative bacteria (Klebsiella pneumoniae) was increased in serglycin knockout mice compared with wild-type mice, as previously reported for neutrophil elastase knockout mice. Thus, serglycin proteoglycan has an important role in localizing neutrophil elastase in azurophil granules of neutrophils, while localization of other granule proteins must be mediated by other mechanisms.
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PMID:Neutrophil elastase depends on serglycin proteoglycan for localization in granules. 1727 11

The treatment of children affected by severe congenital neutropenia (SCN) with G-CSF strongly reduces the risk of sepsis by reversing neutropenia. However, SCN patients who respond to the treatment with the growth factor still have an elevated risk of succumbing to sepsis. Because the disease is usually caused by heterozygous mutations of ELA2, a gene encoding for neutrophil elastase (NE), we have investigated in G-CSF-responder and nonresponder patients affected by SCN the expression of polypeptides that constitute the antimicrobial machinery of these cells. In peripheral blood-derived neutrophils of patients with heterozygous mutations of ELA2 who were treated with G-CSF, NE was nearly absent as detected by immunofluorescence and immunoblotting, suggesting that production of the mutant protein interferes with normal gene expression. This defect was associated with abnormal expression of other granule-associated proteins such as myeloperoxidase, lactoferrin, cathepsin G, and human-neutrophil-peptide. Moreover, in one patient with partial response to G-CSF, we observed an impairment of neutrophil antimicrobial activity against Candida albicans, and, to a lower extent against Escherichia coli. Thereby, we propose that the treatment with G-CSF is not sufficient to correct all of the functional deficiency of neutrophils, and this might account for the consistent risk of infections observed in SCN patients.
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PMID:G-CSF treatment of severe congenital neutropenia reverses neutropenia but does not correct the underlying functional deficiency of the neutrophil in defending against microorganisms. 1788 43

We found that lymphoid enhancer-binding factor 1 (LEF-1) is a decisive transcription factor in granulopoiesis controlling proliferation, proper lineage commitment, and granulocytic differentiation via regulation of its target genes C/EBP-alpha, cyclin D1, c-myc, and survivin. Myeloid progenitor cells of patients with severe congenital neutropenia (CN) showed a severe downregulation of LEF-1 and its target genes expression. Expression of neutrophil elastase (NE) is also severely reduced in CN myeloid progenitors. Intriguingly, ELA2 gene promoter is positively regulated by direct binding of LEF-1 or LEF-1 target gene C/EBP-alpha. In summary we demonstrated that LEF-1 is not only crucial in lymphopoiesis, but also in myelopoiesis, documenting new functions of LEF-1.
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PMID:LEF-1 is a decisive transcription factor in neutrophil granulopoiesis. 1736 Jul 96

Heterozygous mutations of ELA2, encoding the protease neutrophil elastase (NE), cause either autosomal dominant cyclic neutropenia or severe congenital neutropenia (SCN). Three hypotheses have been proposed for how allelic mutations produce these different disorders: 1) disruption of proteolytic activity; 2) mislocalization of the protein; or 3) destabilization of the protein resulting in induction of the unfolded protein response. As with other dominant diseases with reduced reproductive fitness, sporadic cases can result from new mutations not inherited from either parent. Here we report an exceptional genetic phenomenon in which both a cyclic neutropenia patient and an SCN patient each possess two new ELA2 mutations. Because of the rarity of the phenomenon, we investigated the origins of the mutations and found that both arise nonmosaically and in cis from the paternally-inherited allele. Moreover, these cases offer a unique opportunity to investigate molecular pathways distinguishing these two forms of hereditary neutropenia. We have characterized the mutants separately and in combination, with respect to their effects on proteolysis, subcellular trafficking, and induction of the unfolded protein response. Each pair of mutations acts more or less additively to produce equivalent net effects on reducing proteolytic activity and induction of the unfolded protein response, yet each has different and somewhat opposing effects on disturbing subcellular localization, thus offering support for a role for protein mistrafficking as a disease mechanism.
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PMID:Double de novo mutations of ELA2 in cyclic and severe congenital neutropenia. 1743 13

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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PMID:Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. 1776 33


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