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ELA2

Official Full Name
elastase, neutrophil expressed
Organism
Homo sapiens
GeneID
1991
Background
Elastases form a subfamily of serine proteases that hydrolyze many proteins in addition to elastin. Humans have six elastase genes which encode structurally similar proteins. The encoded preproprotein is proteolytically processed to generate the active protease. Following activation, this protease hydrolyzes proteins within specialized neutrophil lysosomes, called azurophil granules, as well as proteins of the extracellular matrix. The enzyme may play a role in degenerative and inflammatory diseases through proteolysis of collagen-IV and elastin. This protein also degrades the outer membrane protein A (OmpA) of E. coli as well as the virulence factors of such bacteria as Shigella, Salmonella and Yersinia. Mutations in this gene are associated with cyclic neutropenia and severe congenital neutropenia (SCN). This gene is present in a gene cluster on chromosome 19. [provided by RefSeq, Jan 2016]
Synonyms
GE; NE; HLE; HNE; ELA2; SCN1; PMN-E;
Bio Chemical Class
Peptidase
Protein Sequence
MTLGRRLACLFLACVLPALLLGGTALASEIVGGRRARPHAWPFMVSLQLRGGHFCGATLIAPNFVMSAAHCVANVNVRAVRVVLGAHNLSRREPTRQVFAVQRIFENGYDPVNLLNDIVILQLNGSATINANVQVAQLPAQGRRLGNGVQCLAMGWGLLGRNRGIASVLQELNVTVVTSLCRRSNVCTLVRGRQAGVCFGDSGSPLVCNGLIHGIASFVRGGCASGLYPDAFAPVAQFVNWIDSIIQRSEDNPCPHPRDPDPASRTH
Open
Disease
Acute respiratory distress syndrome, Anterior uveitis, Atopic eczema, Bronchiectasis, Chronic obstructive pulmonary disease, Crohn disease, Cystic fibrosis, Emphysema, Hepatic fibrosis/cirrhosis, Inflammatory spondyloarthritis, Injury, Intrathoracic organs injury, Multiple sclerosis, Myocardial infarction, Phlegmy cough, Pneumonia, Postoperative inflammation, Psoriatic arthritis, Pulmonary disease, Pyoderma gangrenosum, Rheumatoid arthritis, Sepsis, Ulcerative colitis
Approved Drug
0
Clinical Trial Drug
11 +
Discontinued Drug
14 +

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Detailed Information

Elastase hydrolyzes several proteins, not only elastin but also several components of the extracellular matrix since it belongs to the serine protease family. Six elastase genes in humans encode structurally identical preproteins that, via proteolytic processes, become active enzymes, therefore playing important roles in the immune system. Elastase predominantly resides in the azurophilic granules, special lysosomes of neutrophils, where it can hydrolyze proteins associated with immune responses, participating in physiological processes like immune defense and inflammatory responses.

Structure and Function of the Elastase Gene

The elastase gene is located on chromosome 19 and belongs to a gene cluster that includes functionally related genes such as PRTN3 and NAZC. The primary function of elastase is to degrade elastin and type IV collagen in the extracellular matrix through its serine protease activity, thus influencing various diseases. For instance, in degenerative and inflammatory diseases, elastase activity may lead to the degradation of collagen and elastin, exacerbating pathological changes. Elastase can also degrade outer membrane proteins of certain bacteria, such as outer membrane protein A (OmpA) of Escherichia coli, and virulence factors of Shigella, Salmonella, and Yersinia, thereby affecting the pathogenicity of these pathogens.

Relationship Between Elastase and the Immune System

Elastase plays a vital role in neutrophils, exerting antibacterial actions by dissolving the outer membrane proteins of pathogenic cells. Studies have demonstrated that elastase displays bactericidal action against Escherichia coli but has a lower effect on Staphylococcus aureus. Apart from direct antibacterial action, elastase modulates the roles of monocytes, granulocytes, and natural killer cells, therefore controlling immunological response. It can, for instance, limit C5a-dependent neutrophil enzyme release and chemotaxis, hence lowering inflammatory response.

Mutations in the Elastase and Associated Diseases

The most prominent inherited immune system disease that closely relates to mutations in the elastase gene is cyclic neutropenia (CN), followed by severe congenital neutropenia (SCN). Common autosomal dominant genetic condition cyclic neutropenia is typified by cyclical oscillations in neutrophil numbers, usually reaching a nadir about every 21 days, whereupon the counts might plummet to almost zero. Researches show a clear correlation between dominant mutations in the elastase gene and cyclic neutropenia.

In contrast, severe congenital neutropenia presents as persistent neutropenia with arrested neutrophil development, leading to severe deficiencies in immune defense. The genetic basis of SCN is complex, involving mutations in the elastase gene as well as defects in other genes such as HAX1 and G6PC3. These mutations not only affect neutrophil counts but may also cause functional abnormalities, further exacerbating the immune system deficiency.

Figure 1 illustrates the main steps leading to the disruption of NE-mediated granulopoiesis, highlighting neutrophil development stages where differentiation blockades occur, the role of ELANE frameshift mutations in activating cellular surveillance pathways, and the mechanisms by which mutant NE induces neutropenia.Figure 1. Outline of main steps leading to disruption of NE-mediated granulopoiesis. (Mazur A, et al., 2023)

Molecular Mechanisms of Elastase Mutations

Mutations in the elastase gene primarily concentrate in the terminal exons, particularly the fifth exon. Studies have demonstrated that termination codon mutations in the elastase gene result in non-functional proteins, leading to developmental arrest and decreased counts of neutrophils. Termination mutations typically evade cellular quality control mechanisms like nonsense-mediated decay, allowing the production of abnormal proteins that worsen disease symptoms.

Moreover, other mutations in the elastase gene, such as missense or frameshift mutations, can also impact protein function. Inaccurate amino acid sequences could cause a loss of enzymatic activity or change the intracellular location and function of the enzyme, therefore compromising the immune system's capacity to fight infections and raising vulnerability to them.

Potential Roles of the Elastase in Other Diseases

Apart from its function in neutropenia, abnormal expression and deregulation of the elastase gene may help to pathogenize many different medical disorders. For example, in research on the function of elastase in osteoporosis and other bone metabolic disorders Reduced bone density is a common trait of SCN patients that might be related to negative effects from recombinant human granulocyte-stimulating factor (rh-GCSF) therapies. By activating osteoclasts and hence restricting osteoblast activity, G-CSF treatment influences bone metabolism.

Additionally, there is a possible association between elastase gene mutations and tumor development. Long-term immune suppression and abnormalities in neutrophil function may be related to some studies showing a higher incidence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in SCN patients.

Genetic Diversity of the Elastase Gene

Mutations in the elastase gene exhibit significant genetic heterogeneity, with variations in mutation forms among different families and individuals. Genome-wide association studies (GWAS) have identified various mutations related to neutrophil counts and elastase gene functions. Although elastase gene mutations are primary genetic factors for cyclic neutropenia and severe congenital neutropenia, phenotype variations exist among individuals, likely due to interactions with other genes or environmental factors.

Furthermore, GWAS has revealed other genomic regions associated with elastase gene mutations, indicating the existence of genetic modifier genes. These modifier genes may influence the expression or function of the elastase gene, further modulating clinical manifestations of diseases. Therefore, the elastase gene is not only a core gene for cyclic and severe congenital neutropenia, but its mutations also provide clues to the pathogenesis of other related immune disorders.

References:

  1. Dale DC, Makaryan V. ELANE-Related Neutropenia. 2002 Jun 17 [updated 2018 Aug 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024.
  2. Horwitz MS, Corey SJ, et al. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am. 2013 Feb;27(1):19-41, vii.
  3. Mazur A, Skrzeczynska-Moncznik J, et al. Elastase-dependent congenital neutropenia. Rare Dis Orphan Drugs J. 2023;2:1.
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