Alternative titles; symbols
HGNC Approved Gene Symbol: ELANE
SNOMEDCT: 191347008; ICD10CM: D70.4; ICD9CM: 288.02;
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:852,303-856,243 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Neutropenia, cyclic | 162800 | Autosomal dominant | 3 |
| Neutropenia, severe congenital 1, autosomal dominant | 202700 | Autosomal dominant | 3 |
Neutrophil elastase (EC 3.4.21.37) is a serine protease of neutrophil and monocyte granules (Horwitz et al., 1999). Its key physiologic role is in innate host defense, but it can also participate in tissue remodeling and possesses secretagogue actions important to local inflammatory responses (Chua and Laurent, 2006).
Aoki (1978) purified a 31-kD serine protease from human bone marrow cell mitochondria. Both granulocytes and erythroblasts were found to contain the protease medullasin, but it was not detected in lymphocytes or thrombocytes. It was shown to be located on the inner membrane of mitochondria. Nakamura et al. (1987) reported the complete genomic sequence and deduced the amino acid sequence of the medullasin precursor. It contains 267 amino acids, including a possible leader sequence of 29 amino acids.
Fletcher et al. (1987) cloned a cDNA encoding elastase-2 from a human pancreatic cDNA library. Similarities to and differences from elastase-1 (130120) and the chymotrypsins (e.g., 118890) were described.
Kawashima et al. (1987) isolated cDNAs from a human pancreatic cDNA library, which indicated that at least 2 elastase II messages are expressed in pancreas. The 2 human elastases II have been designated IIA and IIB. There is 90% overall homology between the amino acid sequences of these 2 classes of elastase II, which is synthesized as a preproenzyme of 269 amino acids.
Sinha et al. (1987) determined the complete amino acid sequence of human neutrophil elastase. The protein consists of 218 amino acid residues, contains 2 asparagine-linked carbohydrate side chains, and is joined together by 2 disulfide bonds. There is only moderate homology with porcine pancreatic elastase (43%). Okano et al. (1987) showed that the 218-amino acid sequence of human neutrophil elastase is identical to that of medullasin.
Belaaouaj et al. (2000) determined the mechanism of neutrophil elastase-mediated killing of E. coli. They found that neutrophil elastase degraded outer membrane protein A (OmpA), localized on the surface of gram-negative bacteria.
Weinrauch et al. (2002) identified human neutrophil elastase as a key host defense protein in preventing the escape of Shigella from phagocytic vacuoles in neutrophils. Neutrophil elastase degrades Shigella virulence factors at a 1,000-fold lower concentration than that needed to degrade other bacterial proteins. In neutrophils in which neutrophil elastase is inactivated pharmacologically or genetically, Shigella escapes from phagosomes, increasing bacterial survival. Neutrophil elastase also preferentially cleaves virulence factors of Salmonella and Yersinia. Weinrauch et al. (2002) concluded that their findings established neutrophil elastase as the first neutrophil factor that targets bacterial virulence proteins.
Increased leukocyte elastase activity in mice lacking secretory leukocyte protease inhibitor (SLPI; 107285) leads to impaired wound healing due to enhanced activity of transforming growth factor-beta (190180) and perhaps additional mechanisms (Ashcroft et al., 2000). Proepithelin (PEPI; 138945), also known as progranulin, an epithelial growth factor, can be converted to epithelins (EPIs) in vivo. Zhu et al. (2002) found that PEPI and EPIs exert opposing activities. EPIs inhibited the growth of epithelial cells but induced them to secrete the neutrophil attractant interleukin-8 (IL8; 146930), while PEPI blocked neutrophil activation by tumor necrosis factor (TNF; 191160), preventing release of oxidants and proteases. SLPI and PEPI formed complexes, preventing elastase from converting PEPI to EPIs. Supplying PEPI corrected the wound-healing defect in Slpi null mice. The authors concluded that SLPI/elastase act via PEPI/EPIs to operate a switch at the interface between innate immunity and wound healing.
The fusion protein PML (102578)-RARA (180240), which is generated by the t(15;17)(q22;q11.2) translocation associated with acute promyelocytic leukemia (APL; 612376), initiates APL when expressed in the early myeloid compartment of transgenic mice. Lane and Ley (2003) found that PML-RARA was cleaved in several positions by a neutral serine protease in a human myeloid cell line; purification revealed that the protease was ELA2. Immunofluorescence localization studies suggested that cleavage of PML-RARA must have occurred within the cell, perhaps within the nucleus. The functional importance of ELA2 for APL development was assessed in Ela2-deficient mice. More than 90% of bone marrow PML-RARA-cleaving activity was lost in the absence of Ela2, and Ela2-deficient animals, but not cathepsin G (CTSG; 116830)-deficient animals, were protected from APL development. The authors determined that primary mouse and human APL cells also contained ELA2-dependent PML-RARA-cleaving activity. Lane and Ley (2003) concluded that, since ELA2 is maximally produced in promyelocytes, it may play a role in APL pathogenesis by facilitating the leukemogenic potential of PML-RARA.
Using reporter gene assays in transfected NIH3T3 mouse fibroblasts, Salipante et al. (2009) found that nuclear ELA2 potentiated transcriptional repression by GFI1 (600871). ELA2 did not function independently as a transcriptional repressor, and corepression with GFI1 did not require proteolytically active ELA2.
Using the LSL-Kras-G12D (191170.0005) model of mouse lung adenocarcinoma (211980), Houghton et al. (2010) found that mutant mice who were also Elane -/- had markedly decreased tumor burden compared to Elane +/+ mice. All LSL-Kras/Elane +/+ mice died, whereas none of the Elane -/- mice died in the study period. In vitro studies in human and mouse adenocarcinoma cells showed that neutrophil elastase directly induced tumor cell proliferation at physiologic levels by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS1; 147545). Degradation of IRS1 was associated with increased interaction between PI3K (see 171834) and the potent mitogen PDGFR (173410), skewing the PI3K axis toward tumor cell proliferation. The findings identified IRS1 as a key regulator of PI3K within malignant cells.
Using yeast 2-hybrid analysis, in vitro pull-down assays, and in vivo immunoprecipitation experiments, Duan et al. (2004) demonstrated that human NOTCH2NLA (618023) interacted with NE containing a processed N terminus and an intact C terminus. The interaction was mediated by the C terminus of NE and the C-terminal 24-amino acid (C24) domain of NOTCH2NLA. NE proteolytically cleaved NOTCH2NLA within its EGF repeats in vitro and in vivo, and the C24 domain of NOTCH2NLA appeared to provide resistance to NE protease activity. In vitro analyses showed that NOTCH2NLA repressed the transcriptional activities of Notch proteins. Disease-causing NE mutants disrupted interaction of NE with NOTCH2NLA, impaired proteolysis of NOTCH2NLA and NOTCH2 (600275), and interfered with NOTCH2 signaling.
Role in Human Immunodeficiency Virus-1 Infection
Bristow et al. (1995) found that human, but not murine, epithelial and leukocyte elastase bound the fusion domain of human immunodeficiency virus (HIV)-1 gp160 and interacted with a pentapeptide representative of the HIV-1 fusion domain. HIV-1 infectivity was blocked during, but not after, the initial contact between virus and cells. Bristow et al. (1995) suggested that the elastase present on T-cell membranes participates in permissiveness of host cells to infection.
Bristow (2001) found that decreased HIV infectivity correlated significantly with decreased cell surface expression of HLE on monocytes but not lymphocytes. Decreased levels of alpha-1-antitrypsin (AAT; 107400), also known as protease inhibitor (PI), correlated with increased cell surface HLE expression and increased HIV infectivity.
Bristow et al. (2001) showed that decreased HIV viral load correlated with decreased circulating PI. Furthermore, asymptomatic patients manifested deficient levels of active PI. Bristow et al. (2001) noted that deficient levels of PI lead to degenerative lung diseases and suggested that preventing PI deficiency may prevent HIV-associated pathophysiology.
Using subclones of monocytic cell lines, Bristow et al. (2003) showed that HLE localized to the cell surface, but not granules, of HIV-1-permissive clones, and to the granules, but not the cell surface, of HIV-1-nonpermissive clones. Stimulation of nonpermissive clones with lipopolysaccharide and LBP (151990), followed by exogenous PI, induced cell surface HLE expression, resulting in susceptibility to HIV infection. PI appeared to promote HIV coreceptor colocalization with surface HLE, thus permitting HIV infectivity.
Zimmer et al. (1992) demonstrated that the genes encoding azurocidin (NAZC; 162815), proteinase-3 (PRTN3; 177020), and neutrophil elastase each have 5 exons. All 3 genes are expressed coordinately and their protein products are packaged together at high levels into azurophil granules during neutrophil differentiation. Belaaouaj et al. (1997) demonstrated that the murine homolog of human ELA2 also contains 5 exons.
Zimmer et al. (1992) showed that the NAZC, PRTN3, and ELA2 genes are within an approximately 50-kb cluster on chromosome 19pter.
By interphase studies with differentially labeled probes for fluorescence in situ hybridization, Pilat et al. (1994) demonstrated that ELA2 is in a gene cluster on 19p13.3 with azurocidin, proteinase-3, and granzyme M (600311).
By interspecific backcross analysis, Belaaouaj et al. (1997) mapped the mouse Ela2 gene to chromosome 10.
Cyclic neutropenia (162800), also known as cyclic hematopoiesis, is an autosomal dominant disorder in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes, and reticulocytes also cycle with the same frequency. Horwitz et al. (1999) used a genomewide screen and positional cloning to map the locus to 19p13.3. They identified 7 different single-basepair substitutions in the ELA2 gene, each on a unique haplotype, in 13 of 13 families, as well as a new mutation in a sporadic case (e.g., 130130.0001-130130.0005). Neutrophil elastase is a target for protease inhibition by alpha-1-antitrypsin (AAT; 107400), and its unopposed release destroys tissue at sites of inflammation. Horwitz et al. (1999) hypothesized that a perturbed interaction between neutrophil elastase and serpins or other substrates may regulate mechanisms governing the clock-like timing of hematopoiesis.
After mutations in the ELA2 gene were identified as the basis of autosomal dominant cyclic neutropenia, Dale et al. (2000) hypothesized that congenital neutropenia (202700) is also due to mutation in this gene. In cyclic neutropenia, the mutations appeared to cluster near the active site of the molecule, whereas the opposite face was predominantly affected by the mutations found in congenital neutropenia. Their studies revealed that 22 of 25 patients with congenital neutropenia had 18 different heterozygous mutations. All 4 patients with cyclic neutropenia and none of 3 patients with Shwachman-Diamond syndrome (260400) had mutations of the ELA2 gene. In the congenital neutropenia patients, 5 different mutations were found in families with 2 or more affected members. Three instances of father-daughter pairs, 1 mother-son pair, and 1 mother with 2 affected sons by different fathers suggested autosomal dominant inheritance.
Because all of the mutations in the ELA2 gene associated with severe congenital neutropenia had been heterozygous, Ancliff et al. (2001) conducted a study to determine whether mutations in ELA2 could account for the disease phenotype in classic autosomal recessive severe congenital neutropenia (Kostmann disease; 610738), as well as in the sporadic and autosomal dominant types. They used direct automated sequencing to study all 5 exons of ELA2 and their flanking introns in 18 patients (3 autosomal recessive, 5 autosomal dominant from 3 kindreds, and 10 sporadic). No mutations were found in the autosomal recessive families. A point mutation was identified in 1 of 3 autosomal dominant families, and a base substitution was identified in 8 of 10 patients with the sporadic form, although 1 of the 8 was shown to have a low frequency polymorphism. These results suggested that mutations in ELA2 are not responsible for classic autosomal recessive Kostmann disease, but provided further evidence for the role of ELA2 in the autosomal dominant form of severe congenital neutropenia.
Ancliff et al. (2002) described the case of a healthy father of a patient who was demonstrated to be mosaic for his daughter's cys42-to-arg ELA2 mutation (130130.0009). Semiquantitative PCR showed that approximately half of his T cells carried the mutation, in contrast to less than 10% of neutrophils. Individual hematopoietic colonies grown from peripheral blood were heterozygous for the mutation or were homozygous wildtype. The results demonstrated that precursors containing the mutation are selectively lost during myelopoiesis or fail to develop into neutrophils. Ancliff et al. (2002) stated that this was the first in vivo confirmation of the pathogenic nature of elastase mutations in humans. The normal neutrophil count in the father suggested that the mutant elastase does not have paracrine effects.
Thusberg and Vihinen (2006) reported detailed bioinformatic analyses of 32 different pathogenic missense mutations in the ELA2 gene. Using 31 different analytic methods, the authors found that different mutations resulted in diverse deleterious effects on protein structure and function, including changes in electrostatic surface potential, contacts and stability, and aggregation, among other changes. There were no obvious genotype/phenotype correlations to explain the phenotypic expression of cyclic versus congenital neutropenia.
Salipante et al. (2007) reported 2 unrelated patients with cyclic neutropenia and severe congenital neutropenia, respectively, who each had 2 de novo mutations in cis in the ELA2 gene (see, e.g., 130130.0010). In both patients, the 2 mutations were paternally derived and likely arose during spermatogenesis. Functional expression studies showed reduced proteolytic activity, evidence for induction of the unfolded protein response, and disturbed subcellular localization consistent with protein mistrafficking.
Ishikawa et al. (2008) identified heterozygous mutations in the ELA2 gene in 11 (61%) of 18 Japanese patients with severe congenital neutropenia. Five (28%) patients had SCN3 (610738) due to mutation in the HAX1 gene (605998).
Grenda et al. (2007) demonstrated significant activation of the unfolded protein response (UPR) and cellular apoptosis in cells derived from patients with SCN1 and in human granulocyte precursors specifically transfected with SCN1-associated ELA2 mutations, including V72M (130130.0007), P110L (130130.0006), and G185R (130130.0011). The UPR response was assessed by increased expression of XBP1 (194355) and HSPA5 (138120). Milder effects were observed with the cyclic neutropenia-associated R191Q (130130.0001) mutation. There was no evidence for protein mistrafficking within the cell. The findings indicated that the magnitude of UPR activation and apoptosis induced by ELA2 mutations correlated with the phenotypic severity. Grenda et al. (2007) concluded that ELA2-related disorders result from accumulation of misfolded mutant proteins, activation of the UPR, and cellular apoptosis, consistent with a toxic dominant-negative cell intrinsic effect.
Rosenberg et al. (2007) reported that 2 of 4 SCN1 patients with the G185R mutation developed myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) by 15 years follow-up, whereas none of 7 patients with the P110L mutation or 5 patients with the S97L (130130.0008) mutation had developed MDS/AML.
Germeshausen et al. (2013) found 116 different ELANE mutations in 162 (41%) of 395 patients with congenital neutropenia and 26 mutations in 51 (55%) of 92 patients with cyclic neutropenia, including 69 novel mutations. The mutations were spread throughout the gene sequence. Cyclic neutropenia-associated mutations were predicted to be more benign than congenital neutropenia-associated mutations, but the mutation severity largely overlapped. The frequency of acquired CSF3R (138971) mutations, malignant transformation, and the need for hematopoietic stem cell transplantation were significantly higher in congenital neutropenia patients with ELANE mutations than in ELANE mutation-negative patients. Cellular elastase activity was reduced in neutrophils from all patients, irrespective of the mutation status. In congenital neutropenia, enzymatic activity was significantly lower in patients with ELANE mutations compared with those with wildtype ELANE. Despite differences in the spectrum of mutations, type or localization of mutation only partially determines the clinical phenotype. Thus, there were no apparent genotype/phenotype correlations. The report also indicated that specific ELANE mutations have limited predictive value for leukemogenesis; the risk for leukemia was correlated with disease severity rather than with occurrence of an ELANE mutation.
Bullous pemphigoid (BP) is an autoimmune skin disease characterized by subepidermal blisters and autoantibodies against 2 hemidesmosome-associated proteins, BP180 (COL17A1; 113811) and BP240 (BPAG1; 113810). The immunopathologic features of BP can be reproduced in mice by passive transfer of anti-BP180 antibodies. Lesion formation in this animal model depends on complement activation and neutrophil recruitment. Liu et al. (2000) investigated the role of neutrophil elastase in antibody-induced blister formation in experimental BP. Abnormally high levels of caseinolytic activity, consistent with NE, were detected in extracts of lesional skin and blister fluid of mice injected with anti-BP180 IgG. In NE-null (NE -/-) mutant mice, the pathogenic anti-BP180 IgG failed to induce subepidermal blistering. Wildtype mice given NE inhibitors, but not mice given cathepsin G/chymase inhibitors, were resistant to the pathogenic activity of anti-BP180 antibodies. Incubation of murine skin with NE induced BP-like epidermal-dermal detachment. Finally, Liu et al. (2000) showed that NE cleaved BP180 in vitro and in vivo. These results implicated NE directly in the dermal-epidermal cleavage induced by anti-BP180 antibodies in the experimental BP model.
Using mice deficient in Ctsg and/or Ela2, Reeves et al. (2002) confirmed data originally generated by Tkalcevic et al. (2000) and Belaaouaj et al. (1998) that Ctsg -/- mice resist Candida but not Staphylococcal infection, whereas the reverse is true in Ela2 -/- mice. Both organisms were more virulent in double-knockout mice. Purified neutrophils from these mice mirrored these results in vitro in spite of exhibiting normal phagocytosis, degranulation, oxidase activity, superoxide production, and myeloperoxidase (MPO; 606989) activity. Reeves et al. (2002) hypothesized that reactive oxygen species (ROS) and proteases act together since deficiencies in either lead to comparable reductions in killing efficiency. They determined that conditions in the phagocytic vacuole after activation provoke the influx of enormous concentrations of ROS compensated by a surge of K+ ions crossing the membrane in a pH-dependent manner. The resulting rise in ionic strength induces the release of cationic granule proteins, including Ctsg and Ela2, from the highly charged anionic sulfated proteoglycan matrix within the granules. Reeves et al. (2002) concluded that it is essential for the volume of the vacuole to be restricted for the requisite hypertonicity to develop. They proposed that disruption of the integrity of the cytoskeletal network by microbial products could offer a mechanism of virulence by inhibiting the activation of granule proteins.
Benson et al. (2003) stated that over 20 different mutations of neutrophil elastase had been identified, but their consequences had been elusive because they confer no consistent effects on enzymatic activity (Li and Horwitz, 2001). The autosomal recessive disorder canine cyclic hematopoiesis (Lothrop et al., 1987), also known as gray collie syndrome, is not caused by mutations in neutrophil elastase. Benson et al. (2003) showed that homozygous mutation of the gene encoding the dog adaptor protein complex-3 (AP3) beta-subunit (AP3B1; 603401), directing trans-Golgi export of transmembrane cargo proteins to lysosomes, causes canine cyclic hematopoiesis. C-terminal processing of neutrophil elastase exposes an AP3 interaction signal responsible for redirecting neutrophil elastase trafficking from membranes to granules. Disruption of either neutrophil elastase or AP3 perturbs the intracellular trafficking of neutrophil elastase. Most mutations in ELA2 that cause human cyclic hematopoiesis prevent membrane localization of neutrophil elastase, whereas most mutations in ELA2 that cause severe congenital neutropenia (SCN) lead to exclusive membrane localization.
The elastase secreted by leukocytes is a serine protease inhibitable by alpha-1-protease inhibitor (107400), whereas the elastase secreted by macrophages (MMP12; 601046) is a metalloprotease not inhibitable by alpha-1-protease inhibitor (Rosenbloom, 1984).
In 3 of 13 families with cyclic neutropenia (162800), Horwitz et al. (1999) demonstrated a G-to-A transition in the ELA2 gene at the second position in codon 191 (numbering from the first residue after the presignal peptide had been cleaved), resulting in an arg191-to-gln amino acid substitution.
In 2 of 13 families with cyclic neutropenia (162800), Horwitz et al. (1999) found a G-to-T transversion in the ELA2 gene at the wobble position of codon 177, resulting in replacement of the normal leucine with a phenylalanine.
In 1 family, Horwitz et al. (1999) demonstrated that cyclic neutropenia (162800) was due to a C-to-T transition in the ELA2 gene resulting in an ala32-to-val amino acid substitution.
In 2 of 13 families and in a sporadic new mutation case with cyclic neutropenia (162800), Horwitz et al. (1999) found a splice donor mutation of intron 4 of the ELA2 gene, a transition of the invariant guanine to an adenine at the +1 position. The parents were not affected and did not carry the mutation, and paternity was confirmed.
In 3 families with cyclic neutropenia (162800), Horwitz et al. (1999) noted a G-to-A transition at the +5 position of intron 4 of the ELA2 gene, where guanine is present in 84% of cases.
In 4 unrelated patients with congenital neutropenia (SCN1; 202700), Dale et al. (2000) found heterozygosity for a 15862C-T transition in genomic DNA causing a pro110-to-leu (P110L) amino acid substitution. One of the families had an affected mother and 2 affected sons with different fathers, supporting autosomal dominant inheritance. Another family with the P110L mutation had an affected mother and son; another family had an affected father and daughter.
Rosenberg et al. (2007) identified the P110L mutation in 7 of 82 unrelated patients with SCN1. None of the patients had developed MDS/AML at 15 years follow-up.
In 2 unrelated families, Dale et al. (2000) found that patients with congenital neutropenia (SCN1; 202700) were heterozygous for the same 34371G-A substitution in exon 3 of the ELA2 gene, resulting in a val72-to-met (V72M) mutation. In 1 of the families a father and daughter were affected.
Ancliff et al. (2001) commented on the variation in phenotype in patients with the same ELA2 mutation. They reported 2 patients with a C-to-T transition at nucleotide 4495 in exon 4 of the ELA2 gene, resulting in a ser97-to-leu (S97L) substitution. One of the patients, aged 5 years at the time of report, had severe neutropenia (SCN1; 202700) and remained on GCSF therapy with only a modest response. The other patient, aged 13 years at the time of report, had severe neutropenia and recurrent infections until he started GCSF at the age of 4 years. He responded well and needed only a small maintenance dose. GCSF was discontinued when he was 8; he remained free of major infections and had a neutrophil count of approximately 0.5 x 10(9)/L. The authors stated that the difference may reflect the influence of other inherited modifying factors.
Rosenberg et al. (2007) identified the S97L mutation in 5 of 82 unrelated patients with SCN1. None of the patients had developed MDS/AML at 15 years follow-up.
In a child with severe congenital neutropenia (SCN1; 202700), Ancliff et al. (2001) identified heterozygosity for a 1929T-C mutation in the ELA2 gene, resulting in a cys42-to-arg (C42R) substitution. They found mosaicism for the mutation in her healthy father. Approximately half of the father's T cells carried the mutation, in contrast to less than 10% of neutrophils.
In a patient with severe congenital neutropenia (SCN1; 202700), Salipante et al. (2007) identified 2 de novo mutations in the ELA2 gene in cis on the paternal allele. The father was unaffected, and the mutations likely arose during spermatogenesis. The mutations, which were 9 nucleotides apart in exon 3, resulted in val69-to-leu (V69L) and val72-to-leu (V72L) substitutions. Functional expression studies showed that each mutation by itself reduced proteolytic enzyme activity by slightly less than half, but together showed an additive effect with minimal remaining enzyme activity. Nuclear localization studies showed that the V72L mutant distributed to the cytoplasm, whereas the V69L mutant accumulated at the cell surface. The 2 mutations together yielded a compromise with moderate amounts in both the cytoplasm and at the cell surface, as well as some expression in the nucleus. Salipante et al. (2007) concluded that the mutations result in disturbed subcellular protein trafficking. There was also some evidence for induction of the unfolded protein response.
In patients with severe congenital neutropenia (SCN1; 202700), Dale et al. (2000) and Bellanne-Chantelot et al. (2004) identified a heterozygous 4924G-A transition in exon 5 of the ELA2 gene, resulting in a gly185-to-arg (G185R) substitution.
Rosenberg et al. (2007) identified the G185R mutation in 4 of 82 unrelated patients with SCN1. Patients with the G185R mutation had a particularly severe disease course, and 2 developed MDS/AML at 10 and 15 years, respectively.
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