| *300335 | |||||||||||||||||||||||||||||||||
| ANGIOTENSIN I-CONVERTING ENZYME 2; ACE2 | |||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||
| ACEH | |||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: ACE2 | |||||||||||||||||||||||||||||||||
| Cytogenetic location: Xp22.2 Genomic coordinates (GRCh37): X:15,579,155 - 15,620,191 (from NCBI) | |||||||||||||||||||||||||||||||||
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| Cloning | |||||||||||||||||||||||||||||||||
| By EST database searching for sequences showing homology to the zinc metalloprotease angiotensin-I converting enzyme (ACE; 106180) and by screening a human lymphoma cDNA library, Tipnis et al. (2000) cloned a full-length ACE2 cDNA, which they called ACEH, encoding a deduced 805-amino acid protein that shares approximately 40% identity with the N- and C-terminal domains of ACE. ACE2 contains a potential 17-amino acid N-terminal signal peptide and a putative 22-amino acid C-terminal membrane anchor. It has a conserved zinc metalloprotease consensus sequence (HEXXH) and a conserved glutamine residue that is predicted to serve as a third zinc ligand. Northern blot analysis detected high expression of ACE2 in kidney, testis, and heart, and moderate expression in colon, small intestine, and ovary. By quantitative RT-PCR, Harmer et al. (2002) found ACE2 expressed in all 72 human tissues and cells examined except red blood cells. Highest expression was detected in testis, renal and cardiovascular tissues, and in all portions of the gastrointestinal tract, particularly the ilium. Central nervous system and lymphoid tissues expressed relatively low ACE2 levels. Itoyama et al. (2005) cloned full-length ACE2 cDNA from human lung and identified different splicing sites and an alternative 5-prime untranslated exon. RT-PCR detected expression of the alternative 5-prime exon in lung, testis, trachea, bronchial epithelial cells, small intestine, and various major organs. | |||||||||||||||||||||||||||||||||
| Gene Function | |||||||||||||||||||||||||||||||||
| Tipnis et al. (2000) expressed a soluble, truncated form of ACE2 lacking transmembrane and cytosolic domains in CHO cells and found that it produced a glycosylated protein that was able to cleave angiotensin I and angiotensin II (see 106150), but not bradykinin. In the hydrolysis of the angiotensins, ACE2 functioned exclusively as a carboxypeptidase. Tipnis et al. (2000) showed that ACE2 was not inhibited by benzylsuccinate, a carboxypeptidase A inhibitor, or by other ACE inhibitors such as lisinopril. Boehm and Nabel (2002) reviewed the work of Crackower et al. (2002) and others in characterizing ACE2, which has direct effects on cardiac function. ACE2 is expressed predominantly in vascular endothelial cells of the heart and kidney. Whereas ACE converts angiotensin I to angiotensin II, which has 8 amino acids, ACE2 converts angiotensin I to angiotensin 1-9, which has 9 amino acids. Whereas angiotensin II is a potent blood vessel constrictor, angiotensin 1-9 has no effect on blood vessels but can be converted by ACE to a shorter peptide, angiotensin 1-7, which is a blood vessel dilator. Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells. Li et al. (2003) identified ACE2, isolated from SARS coronavirus-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS coronavirus S protein. Li et al. (2003) found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with HIV-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS coronavirus replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Li et al. (2003) concluded that ACE2 is a functional receptor for SARS coronavirus. Jeffers et al. (2004) demonstrated that another human cellular glycoprotein, namely CD209L (605872), can serve as an alternative receptor for the SARS coronavirus. Using retroviral pseudotypes to analyze cell tropism and receptor engagement, Hofmann et al. (2005) found that the S protein of NL63, a novel group I human coronavirus isolated from infants and immunocompromised adults, engaged the SARS receptor ACE2 for cellular entry. They also showed that replication of NL63 depended on ACE2. NL63 did not use CD13 (ANPEP; 151530), the receptor for the closely related group I coronavirus 229E. Neutralization assays demonstrated that sera from adults and children, but not infants, inhibited replication of NL63. In contrast, only a minority of sera inhibited replication of 229E, suggesting that NL63 infection is more frequent and typically occurs during childhood. Kuba et al. (2005) hypothesized that the SARS coronavirus S protein could adversely affect acute lung injury through modulation of ACE2. Pull-down and FACS analyses demonstrated that S protein bound to ACE2 and downregulated ACE2 surface expression. Treatment of wildtype mice with S protein or with its truncated ACE2-binding domain worsened lung function. Acid challenge of these mice further augmented pathology to lung parenchyma. The S protein localized to bronchial epithelial cells, inflammatory exudates, and alveolar pneumocytes. Furthermore, S protein downregulated Ace2 expression in acid-treated wildtype mice and increased lung levels of angiotensin II. Blockage of angiotensin II receptor-1 (AGTR1; 106165), which mediates angiotensin II-induced vascular permeability and severe acute lung injury, attenuated lung injury in S protein-treated mice. Kuba et al. (2005) concluded that SARS coronavirus S protein can exaggerate acute lung failure through deregulation of the renin-angiotensin system, and that lung failure can be rescued by inhibition of AGTR1. | |||||||||||||||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||||||||||||||
| Tipnis et al. (2000) determined that the ACE2 gene contains 18 exons, with some similarity in exon size and organization to those of ACE, and spans approximately 40 kb of genomic DNA. Itoyama et al. (2005) identified an alternative untranslated exon 5-prime to the original exon 1. | |||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||
| Tipnis et al. (2000) mapped the ACE2 gene by sequence similarity to a sequence in GenBank (AC003669) mapping to Xp22. | |||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||
| Itoyama et al. (2005) identified 19 SNPs in the ACE2 gene. A case-control study found no association between these SNPs and SARS in the Vietnamese population. | |||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||
| Crackower et al. (2002) demonstrated that Ace2 maps to a defined quantitative trait locus (QTL) on the X chromosome in 3 different rat models of hypertension. In all hypertensive rat strains, Ace2 mRNA and protein expression were markedly reduced, suggesting that Ace2 is a candidate gene for this QTL. Targeted disruption of Ace2 in mice resulted in a severe cardiac contractility defect, increased angiotensin II (see 106150) levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of Ace on an Ace2 mutant background completely rescues the cardiac phenotype. Crackower et al. (2002) showed that disruption of Acer, a Drosophila Ace2 homolog, resulted in a severe defect of heart morphogenesis. Crackower et al. (2002) concluded that Ace2 is an essential regulator of heart function in vivo. Imai et al. (2005) reported that ACE2 and the angiotensin II type 2 receptor (300034) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE (106180), angiotensin II, and the angiotensin II type 1a receptor (106165), promote disease pathogenesis, induce lung edemas, and impair lung function. Imai et al. (2005) showed that mice deficient for ACE show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Imai et al. (2005) concluded that their data identified a critical function for ACE2 in acute lung injury. Gurley et al. (2006) generated Ace2-deficient mice and found that they were viable, fertile, and had normal cardiac dimensions and function. After acute angiotensin II (AT2) infusion, plasma concentrations of AT2 increased almost 3-fold higher in Ace2-deficient mice than in controls. In a model of AT2-dependent hypertension, blood pressures were substantially higher in the Ace2-deficient mice than in wildtype mice, and severe hypertension in Ace2-deficient mice was associated with exaggerated accumulation of AT2 in the kidney. Although absence of functional ACE2 caused enhanced susceptibility to AT2-induced hypertension, the authors found no evidence for a role of ACE2 in the regulation of cardiac structure or function. Gurley et al. (2006) suggested that ACE2 is a functional component of the renin-angiotensin system, metabolizing AT2 and thereby contributing to the regulation of blood pressure. | |||||||||||||||||||||||||||||||||
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