Alternative titles; symbols
HGNC Approved Gene Symbol: ECE1
Cytogenetic location: 1p36.12 Genomic coordinates (GRCh38): 1:21,217,250-21,345,504 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.12 | ?Hirschsprung disease, cardiac defects, and autonomic dysfunction | 613870 | Autosomal dominant | 3 |
| {Hypertension, essential, susceptibility to} | 145500 | Multifactorial | 3 |
Endothelin-converting enzyme-1 is involved in the proteolytic processing of endothelin-1 (EDN1; 131240), -2 (EDN2; 131241), and -3 (EDN3; 131242) to biologically active peptides.
Schmidt et al. (1994) purified a membrane-bound protease activity from bovine endothelial cells that specifically converts the inactive form to EDN1. The enzyme was cleaved with trypsin and peptide sequencing analysis confirmed it to be a zinc-chelating metalloprotease containing the typical HEXXH (HELTH) motif. RT-PCR and cDNA screens were used to isolate the complete cDNAs of the bovine and human enzymes.
A splice variant of the same cDNA was identified by Shimada et al. (1995) from an umbilical vein endothelial cell library. The authors expressed the protein in COS-1 cells and could detect it in membrane fractions from expressing cells. Yorimitsu et al. (1995) also obtained a human ECE cDNA by screening an ACHN human renal adenocarcinoma library. That cDNA, referred to as AECE, encoded a predicted 770-codon open reading frame which is was different at the amino end from the Shimada et al. (1995) sequence but close to the Schmidt et al. (1994) sequence. The rat ECE and human AECE amino acid sequences were over 96% alike.
The ECE1 gene contains 20 exons and spans over 120 kb (Valdenaire et al., 1999; Funke-Kaiser et al., 2000).
Valdenaire et al. (1995) found that the precursors of the ECE1 a and b isoform mRNAs are transcribed from 2 distinct start sites, upstream from exon 1 and exon 3, respectively. Sequence analysis of the 2 putative promoters revealed the presence of motifs characteristic for several transcription factors. The authors stated that comparison of the ECE gene structure with those of other zinc metalloproteinases, as well as a phylogenetic study, confirmed the existence of a metalloprotease subfamily composed of ECE1, ECE2 (610145), neutral endopeptidase (120520), Kell blood group protein (613883), and 2 bacterial enzymes.
Maggi et al. (2000) demonstrated that in FNC-B4 cells, which are derived from a human fetal olfactory epithelium, both sex steroids and odorants regulate GnRH secretion. They found biologic activity of EDN1 in this GnRH-secreting neuronal cell. In situ hybridization and immunohistochemistry revealed gene and protein expression of EDN1 and ECE1 in both fetal olfactory mucosa and FNC-B4 cells. Experiments with radiolabeled EDN1 and EDN3 strongly indicated the presence of 2 classes of binding sites, corresponding to the ETA (16,500 sites/cell) and the ETB receptors (8,700 sites/cell). Functional studies using selective analogs indicated that these 2 classes of receptors subserve distinct functions in human GnRH-secreting cells. The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion.
Valdenaire et al. (1995) mapped the ECE1 gene to chromosome 1p36 by isotopic in situ hybridization.
By Southern blot analysis of human genomic DNA from human/mouse somatic cell hybrids, Matsuoka et al. (1996) demonstrated that ECE1 maps to chromosome 1. By fluorescence in situ hybridization (FISH), they refined the localization to 1p36.1. By FISH, Albertin et al. (1996) mapped ECE1 to 1p36 and confirmed the localization to chromosome 1 by analysis of monochromosomal hybrids. Radiation hybrid mapping localized the gene tentatively at the border between 1p36.3 and 1p36.2.
Hirschsprung Disease, Cardiac Defects, and Autonomic Dysfunction
Hofstra et al. (1999) described involvement of the ECE1 gene in a patient with skip-lesions Hirschsprung disease, cardiac defects, and autonomic dysfunction (HCAD; 613870). By screening all 19 exons of the gene, using denaturing gradient gel electrophoresis followed by sequencing, they identified a heterozygous C-to-T transition, resulting in the substitution of cysteine for arginine at position 742 (R742C; 600423.0001).
Essential Hypertension
Funke-Kaiser et al. (2003) proposed that ECE1 is a candidate gene for human blood pressure regulation and identified 5 polymorphisms in ECE1 among a cohort of 704 European hypertensive patients. Transient transfection of the reporter constructs containing the -338A allele (600423.0002) showed an increase in promoter activity compared with the wildtype promoter. Electrophoretic mobility shift assays revealed the specific binding of E2F2 (600426), a transcription factor, to both ECE1b promoter sequences, with the -338A allele being associated with an increased affinity to E2F2 compared with -338C. In 100 untreated hypertensive women, both the -338A and -839G (600423.0003) alleles were significantly associated with ambulatory blood pressure values. The authors proposed a link between the cell cycle-associated E2F family and blood pressure regulation via a component of the endothelin system.
Yanagisawa et al. (1998) and Clouthier et al. (1998) showed that mice deficient in either endothelin receptor type A (EDNRA; 131243) or ECE1 develop defects in a subset of cephalic and cardiac neural crest derivatives. Ednra-null mice show defects in craniofacial structures, great vessels, and cardiac outflow tract. Ece1-null mice exhibit a virtually identical phenotype to Ednra-deficient and endothelin-1-deficient embryos due to the absence of biologically active endothelin-1. Ece1-deficient mice lack enteric neurons and epidermal/choroidal melanocytes, reproducing the phenotype of Edn3 (131242) and Ednra knockout mice. Yanagisawa et al. (1998) elaborated on the role of the Edn1/Ednra pathway in the patterning of the aortic arch in mice.
Eckman et al. (2003) found that Ece1 +/- mice had significantly elevated concentrations of both beta-amyloid-40 and beta-amyloid-42 (see APP; 104760) in their brains compared with littermate controls.
Choi et al. (2006) found that doubly transgenic mice expressing an Alzheimer disease (104300)-associated APP mutation and overexpressing PRKCE (176975) had decreased amyloid plaques, plaque-associated neuritic dystrophy, and reactive astrocytosis compared to mice only expressing the APP mutation. There was no evidence for altered APP cleavage in the doubly transgenic mice; instead, overexpression of PRKCE increased the activity of Ece1, which degrades beta-amyloid.
Ortmann et al. (2005) found that expression of Ece1 and Ece2 was increased in nonobese diabetic mice compared with controls.
Hofstra et al. (1999) identified heterozygosity an arg742-to-cys (R742C) mutation in the ECE1 gene in a patient with skip-lesions Hirschsprung disease, cardiac defects, craniofacial abnormalities and other dysmorphic features, and autonomic dysfunction (HCAD; 613870). The patient's parents were not available for testing. Amino acid position 742 is in the vicinity of the active site of ECE1 (Valdenaire et al., 1995). Hofstra et al. (1999) suggested that the R742C mutation was responsible for, or at least contributed to, the phenotype of the patient in view of the function of ECE1 during murine development suggested by mouse models, the overlap in phenotypic features of these mouse models and those of the patient, and the functional consequences of the mutation on enzyme activity. The mutation was thought to lead to the phenotype by resulting in reduced levels of EDN1 and EDN3.
Funke-Kaiser et al. (2003) identified a polymorphism in the 5-prime flanking region of the ECE1 gene, -338C-A, that was associated with ambulatory blood pressure values (see 145500). The polymorphism is located within a putative consensus site for E2F (see 189971) and GATA (see 601656) proteins. The -338A allele was associated with higher daytime and nighttime 24-hour systolic and diastolic blood pressure in nontreated hypertensive women. Transient transfection of the reporter constructs containing the -338A allele showed an increase in promoter activity compared with the wildtype promoter. Electrophoretic mobility shift assays revealed the specific binding of E2F2 (600426), a transcription factor, to both ECE1b promoter sequences, with the -338A allele being associated with an increased affinity to E2F2 compared with -338C.
Funke-Kaiser et al. (2003) identified a polymorphism in the 5-prime flanking region of the ECE1 gene, -839T-G, that was associated with ambulatory blood pressure values (see 145500).
Albertin, G., Rossi, G. P., Majone, F., Tiso, N., Mattara, A., Danieli, G. A., Pessina, A. C., Palu, G. Fine mapping of the human endothelin-converting enzyme gene by fluorescent in situ hybridization and radiation hybrids. Biochem. Biophys. Res. Commun. 221: 682-687, 1996. [PubMed: 8630021] [Full Text: https://doi.org/10.1006/bbrc.1996.0656]
Choi, D.-S., Wang, D., Yu, G.-Q., Zhu, G., Kharazia, V. N., Paredes, J. P., Chang, W. S., Deitchman, J. K., Mucke, L., Messing, R. O. PKC-epsilon increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice. Proc. Nat. Acad. Sci. 103: 8215-8220, 2006. [PubMed: 16698938] [Full Text: https://doi.org/10.1073/pnas.0509725103]
Clouthier, D. E., Hosoda, K., Richardson, J. A., Williams, S. C., Yanagisawa, H., Kuwaki, T., Kumada, M., Hammer, R. E., Yanagisawa, M. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125: 813-824, 1998. [PubMed: 9449664] [Full Text: https://doi.org/10.1242/dev.125.5.813]
Eckman, E. A., Watson, M., Marlow, L., Sambamurti, K., Eckman, C. B. Alzheimer's disease beta-amyloid peptide is increased in mice deficient in endothelin-converting enzyme. J. Biol. Chem. 278: 2081-2084, 2003. [PubMed: 12464614] [Full Text: https://doi.org/10.1074/jbc.C200642200]
Funke-Kaiser, H., Bolbrinker, J., Theis, S., Lemmer, J., Richter, C.-M., Paul, M., Orzechowski, H.-D. Characterization of the c-specific promoter of the gene encoding human endothelin-converting enzyme-1 (ECE-1). FEBS Lett. 466: 310-316, 2000. [PubMed: 10682850] [Full Text: https://doi.org/10.1016/s0014-5793(00)01086-3]
Funke-Kaiser, H., Reichenberger, F., Kopke, K., Herrmann, S.-M., Pfeifer, J., Orzechowski, H.-D., Zidek, W., Paul, M., Brand, E. Differential binding of transcription factor E2F-2 to the endothelin-converting enzyme-1b promoter affects blood pressure regulation. Hum. Molec. Genet. 12: 423-433, 2003. Note: Erratum: Hum. Molec. Genet. 12: 947 only, 2003. [PubMed: 12566389] [Full Text: https://doi.org/10.1093/hmg/ddg040]
Hofstra, R. M. W., Valdenaire, O., Arch, E., Osinga, J., Kroes, H., Loffler, B.-M., Hamosh, A., Meijers, C., Buys, C. H. C. M. A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction. (Letter) Am. J. Hum. Genet. 64: 304-308, 1999. [PubMed: 9915973] [Full Text: https://doi.org/10.1086/302184]
Maggi, M., Barni, T., Fantoni, G., Mancina, R., Pupilli, C., Luconi, M., Crescioli, C., Serio, M., Vannelli, G. B. Expression and biological effects of endothelin-1 in human gonadotropin-releasing hormone-secreting neurons. J. Clin. Endocr. Metab. 85: 1658-1665, 2000. [PubMed: 10770212] [Full Text: https://doi.org/10.1210/jcem.85.4.6565]
Matsuoka, R., Sawamura, T., Yamada, K., Yoshida, M., Furutani, Y., Ikura, T., Shiraki, T., Hoshikawa, H., Shimada, K., Tanzawa, K., Masaki, T. Human endothelin converting enzyme gene (ECE1) mapped to chromosomal region 1p36.1. Cytogenet. Cell Genet. 72: 322-324, 1996. [PubMed: 8641140] [Full Text: https://doi.org/10.1159/000134214]
Ortmann, J., Nett, P. C., Celeiro, J., Traupe, T., Tornillo, L., Hofmann-Lehmann, R., Haas, E., Frank, B., Terraciano. L. M., Barton, M. Endothelin inhibition delays onset of hyperglycemia and associated vascular injury in type I diabetes: evidence for endothelin release by pancreatic islet beta-cells. Biochem. Biophys. Res. Commun. 334: 689-695, 2005. [PubMed: 16009335] [Full Text: https://doi.org/10.1016/j.bbrc.2005.06.140]
Schmidt, M., Kroger, B., Jacob, E., Seulberger, H., Subkowski, T., Otter, R., Meyer, T., Schmalzing, G., Hillen, H. Molecular characterization of human and bovine endothelin converting enzyme (ECE-1). FEBS Lett. 356: 238-243, 1994. [PubMed: 7805846] [Full Text: https://doi.org/10.1016/0014-5793(94)01277-6]
Shimada, K., Matsushita, Y., Wakabayashi, K., Takahashi, M., Matsubara, A., Iijima, Y., Tanzawa, K. Cloning and functional expression of human endothelin-converting enzyme cDNA. Biochem. Biophys. Res. Commun. 207: 807-812, 1995. [PubMed: 7864876] [Full Text: https://doi.org/10.1006/bbrc.1995.1258]
Valdenaire, O., Lepailleur-Enouf, D., Egidy, G., Thouard, A., Barret, A., Vranckx, R., Tougard, C., Michel, J.-B. A fourth isoform of endothelin-converting enzyme (ECE-1) is generated from an additional promoter: molecular cloning and characterization. Europ. J. Biochem. 264: 341-349, 1999. [PubMed: 10491078] [Full Text: https://doi.org/10.1046/j.1432-1327.1999.00602.x]
Valdenaire, O., Rohrbacher, E., Mattei, M.-G. Organization of the gene encoding the human endothelin-converting enzyme (ECE-1). J. Biol. Chem. 270: 29794-29798, 1995. [PubMed: 8530372] [Full Text: https://doi.org/10.1074/jbc.270.50.29794]
Yanagisawa, H., Hammer, R. E., Richardson, J. A., Williams, S. C., Clouthier, D. E., Yanagisawa, M. Role of endothelin-1/endothelin-A receptor-mediated signaling pathway in the aortic arch patterning in mice. J. Clin. Invest. 102: 22-33, 1998. [PubMed: 9649553] [Full Text: https://doi.org/10.1172/JCI2698]
Yanagisawa, H., Yanagisawa, M., Kapur, R. P., Richardson, J. A., Williams, S. C., Clouthier, D. E., de Wit, D., Emoto, N., Hammer, R. E. Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 125: 825-836, 1998. [PubMed: 9449665] [Full Text: https://doi.org/10.1242/dev.125.5.825]
Yorimitsu, K., Moroi, K., Inagaki, N., Saito, T., Masuda, Y., Masaki, T., Seino, S., Kimura, S. Cloning and sequencing of a human endothelin converting enzyme in renal adenocarcinoma (ACHN) cells producing endothelin-2. Biochem. Biophys. Res. Commun. 208: 721-727, 1995. [PubMed: 7695628] [Full Text: https://doi.org/10.1006/bbrc.1995.1397]