Alternative titles; symbols
HGNC Approved Gene Symbol: ANGPT1
Cytogenetic location: 8q23.1 Genomic coordinates (GRCh38): 8:107,249,482-107,497,918 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q23.1 | ?Angioedema, hereditary, 5 | 619361 | Autosomal dominant | 3 |
Angiopoietin-1 is an angiogenic growth factor with antipermeability and antiinflammatory properties (summary by Chen et al., 2010).
TIE2 (TEK; 600221) is a receptor-like tyrosine kinase expressed almost exclusively in endothelial cells and early hematopoietic cells and required for the normal development of vascular structures during embryogenesis. Davis et al. (1996) identified a secreted ligand for TIE2, termed angiopoietin-1, using a novel expression cloning technique that involved intracellular trapping and protection of the ligand in COS cells. The human gene encodes a 498-amino acid polypeptide with predicted coiled-coil and fibrinogen-like domains. The structure of angiopoietin-1 differs from that of known angiogenic factors or other ligands for receptor tyrosine kinases. Although angiopoietin-1 bound and induced the tyrosine phosphorylation of TIE2, it did not directly promote the growth of cultured endothelial cells. However, its expression and close proximity to developing blood vessels implicated angiopoietin-1 in endothelial developmental processes. See also angiopoietin-2 (601922).
Thomson et al. (2017) analyzed expression of Angpt1 in the iridocorneal angle of mouse eyes, and observed that Angpt1 was expressed in the trabecular membrane and in cells adjacent to the outer wall of the Schlemm canal.
Ward et al. (2001) determined that the ANGPT1 gene contains 9 exons and spans 48.3 kb. Exons 1 to 5 encode the N terminus, the coiled-coil domain, and part of the hinge region, and exons 5 to 9 encode the remainder of the hinge region, the fibrinogen (see 134820)-like domain, and the C terminus.
By FISH and radiation hybrid analysis, Cheung et al. (1998) mapped the ANGPT1 gene to 8q22.3-q23. Using radiation hybrid analysis and FISH, Grosios et al. (1999) also mapped the ANGPT1 gene to chromosome 8q22.3-q23. By FISH, Valenzuela et al. (1999) mapped the ANGPT1 gene to 8q22 in a region that shows homology of synteny to mouse chromosome 15, where they mapped the mouse Angpt1 gene. However, by indirect in situ PCR and FISH, Marziliano et al. (1999) mapped the Angpt1 gene in the mouse to chromosome 9E2.
Folkman and D'Amore (1996) pointed out that vascular abnormality in both mice and humans is defined by a receptor-ligand system on the vascular endothelial cell. An apparent defect in vascular remodeling can result from an activating mutation of the receptor (Vikkula et al., 1996), from the absence of the ligand (Suri et al., 1996), or from a deficiency of the TIE2 receptor itself (Sato et al., 1995). However, while each situation reveals a general abnormality in vascular remodeling, there may be subtle but important differences.
To explore the possibility that VEGF (192240) and angiopoietins collaborate during tumor angiogenesis, Holash et al. (1999) analyzed several different murine and human tumor models. The apparent association of tumor vessel regression, apoptosis, and disruption of endothelial cell interactions with support cells in rat C6 gliomas raised the possibility that blockade of the stabilizing action of Ang1 might be contributing to tumor vessel regression. Consistent with this possibility, Holash et al. (1999) noted that angiopoietin-1 was antiapoptotic for cultured endothelial cells and expression of its antagonist angiopoietin-2 was induced in the endothelium of co-opted tumor vessels before their regression. Diffuse angiopoietin-1 expression in human tumors resembled that seen in the rat model. Holash et al. (1999) suggested that a subset of tumors rapidly co-opts existing host vessels to form an initially well vascularized tumor mass. Perhaps as part of a host defense mechanism there is widespread regression of these initially co-opted vessels, leading to a secondarily avascular tumor and a massive tumor cell loss. However, the remaining tumor is ultimately rescued by robust angiogenesis at the tumor margin.
Loughna and Sato (2001) showed that the combinatorial function of angiopoietin-1 and the orphan receptor TIE1 (600222) is critical for the development of the right-hand side venous system but is dispensable for the left-hand side venous system. This finding revealed the existence of a distinct genetic program for the establishment of the right-hand side and left-hand side vascular networks well before the network asymmetry becomes morphologically discernible.
Geva et al. (2002) investigated VEGFA, ANGPT1, and ANGPT2 transcript profiles, and the protein products that they encode, in placentas from normotensive pregnancies throughout pregnancy. Quantitative real-time PCR analysis demonstrated that VEGFA and ANGPT1 mRNA increased in a linear pattern by 2.5% (not significant) and 2.8%/week (P = 0.034), respectively, whereas ANGPT2 decreased logarithmically by 3.5%/week (P = 0.0003). ANGPT2 mRNA was 400- and 100-fold higher than that of ANGPT1 and VEGFA, respectively, in the first trimester and declined to 20-fold and 7-fold in the third. In situ hybridization and immunohistochemical studies revealed that VEGFA was localized in cyto- and syncytiotrophoblast and perivascular cells, whereas ANGPT1 and ANGPT2 were only in syncytiotrophoblast and perivascular cells in the immature intermediate villi during the first and second trimesters, and mature intermediate and terminal villi during the third trimester. The authors concluded that these molecules may play important roles in placental biology and chorionic villus vascular development and remodeling in an autocrine/paracrine manner.
Interaction of hematopoietic stem cells (HSCs) with their particular microenvironments, known as stem cell niches, is critical for adult hematopoiesis in bone marrow. Arai et al. (2004) demonstrated that HSCs expressing the receptor tyrosine kinase TIE2 are quiescent and antiapoptotic and comprise a side population of HSCs that adhere to osteoblasts in the bone marrow niche. The interaction of TIE2 with its ligand, ANG1, induced cobblestone formation of HSCs in vitro and maintained in vivo long-term repopulating activity of HSCs. Furthermore, ANG1 enhanced the ability of HSCs to become quiescent and induced adhesion to bone, resulting in protection of the HSC compartment from myelosuppressive stress. These data suggested that the TIE2/ANG1 signaling pathway plays a critical role in the maintenance of HSCs in a quiescent state in the bone marrow niche.
Independently, Fukuhara et al. (2008) and Saharinen et al. (2008) showed that ANG1 bridged TIE2 molecules on the surface of adjacent endothelial cells at cell-cell contacts. In contrast, extracellular matrix-bound ANG1 located TIE2 at cell-substratum contacts in isolated cells. Fukuhara et al. (2008) reported that TIE2 preferentially activated AKT (see 164730) signaling at cell-cell contacts and ERK (see MAPK1; 176948) signaling at cell-substratum contacts. Saharinen et al. (2008) found that ANG1 induced phosphorylation of TIE2-associated eNOS (NOS3; 163729), a downstream substrate of AKT, in intercellular contacts of confluent cells. The authors concluded that the cellular microenvironment determines TIE2 signaling between activated angiogenic endothelial cells and quiescent endothelium.
Chen et al. (2010) found that ANGPT1 is regulated by the microRNA mir211 (613753).
Hereditary Angioedema 5
In 4 affected women from a 3-generation Italian family with hereditary angioedema-5 (HAE5; 619361), Bafunno et al. (2018) identified a heterozygous missense mutation in the ANGPT1 gene (A119S; 601667.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient plasma showed normal levels of ANGPT1, but there was a reduction of multimeric forms compared to wildtype. The mutant protein also showed decreased binding to its membrane receptor TIE2. Similar results were obtained by expression of the mutation in HEK293 cells. Bafunno et al. (2018) hypothesized that the altered ANGPT1 function affects bradykinin-mediated endothelial permeability.
Associations Pending Confirmation
For discussion of a possible association between variation in the ANGPT1 gene and susceptibility to stroke, see 601367.
For discussion of a possible association between primary congenital glaucoma (see GLC3A, 231300) and variation in the ANGPT1 gene, see 601667.0001.
Suri et al. (1996) showed that mice engineered to lack angiopoietin-1 display angiogenic defects reminiscent of those previously seen in mice lacking Tie2, demonstrating that angiopoietin-1 is a primary physiologic ligand for Tie2 and that it has critical in vivo angiogenic actions that are distinct from vascular endothelial growth factor (VEGF; 192240) and that are not reflected in the classic in vitro assays used to characterize VEGF. They concluded that angiopoietin-1 appears to play a crucial role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme.
Targeted gene inactivation studies in mice show that vascular endothelial growth factor is necessary for the early stages of vascular development and that angiopoietin-1 is required for the later stages of vascular remodeling. Suri et al. (1998) showed that transgenic overexpression of angiopoietin-1 in the skin of mice produces larger, more numerous, and more highly branched vessels. These results raised the possibility that angiopoietins can be used, alone or in combination with VEGF, to promote therapeutic angiogenesis.
Thurston et al. (1999) compared transgenic mice overexpressing either Vegf or Ang1 in the skin. Vegf-induced blood vessels were leaky, whereas those induced by Ang1 were not. Moreover, vessels in Ang1-overexpressing mice were resistant to leaks caused by inflammatory agents. Coexpression of Ang1 and Vegf had an additive effect on angiogenesis but resulted in leakage-resistant vessels typical of Ang1. Thurston et al. (1999) concluded that ANG1, therefore, may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated VEFG and, in combination with VEGF, for promoting growth of nonleaky vessels.
Thomson et al. (2017) generated mice with conditional knockout of Angpt1 and/or Angpt2 (601922), and observed that double-knockout mice showed complete absence of the Schlemm canal (SC), and Angpt1 knockouts exhibited a severely hypoplastic SC, characterized by gaps and discontinuous isolated canal segments. In contrast, the Angpt2 knockouts showed no morphologic defects, demonstrating that Angpt1 is the primary TEK ligand in the iridocorneal angle. The developmental failure of the SC in the Angpt1 knockout mice appeared to occur through 2 separate but related processes: there was reduced sprouting from the limbal vascular plexus, as well as decreased proliferation of the vascular sprouts, which form the SC.
Thomson et al. (2020) studied Angpt1 conditional knockout mice, which developed a hypomorphic Schlemm canal, rapidly developed bilateral elevated intraocular pressure, and exhibited buphthalmos by 6 months. The persistent ocular hypertension beginning in the first month after birth resulted in decreased visual acuity with age due to glaucomatous neuropathy. In the neural retina, the authors identified marked and specific loss of the retinal ganglion cells, whereas other retinal neurons exhibited largely normal morphology and patterning. Electroretinogram recordings demonstrated reduced scotopic threshold response, further indicating loss of retinal ganglion cell function. The authors concluded that Angpt1 conditional knockout mice are a potentially useful model for high-pressure open-angle glaucoma.
This variant is classified as a variant of unknown significance because its contribution to primary congenital glaucoma (see GCL3A, 231300) has not been confirmed.
From a cohort of 284 families with primary congenital glaucoma (PCG), negative for mutation in the most commonly mutated PCG-associated genes, Thomson et al. (2017) identified 3 unrelated patients who were heterozygous for mutations in the ANGPT1 gene. One was a male patient (PCG family 1) with onset of disease at age 2 years, who had a c.1480C-T transition in exon 9 of ANGPT1, resulting in an arg494-to-ter (R494X) substitution within the fibrinogen-like domain, located just 5 residues before the normal termination codon. He inherited the mutation from his unaffected 41-year-old mother. The second proband (PCG family 2), who had onset of disease at birth, inherited a Q236X mutation from her unaffected father, and her unaffected sister also carried the variant. The third proband (PCG family 3), who also had onset of disease at birth, was heterozygous for a missense variant (K249R) in ANGPT1; no segregation information was reported for that family. Analysis of the R494X mutant in transfected cells demonstrated that the mutant protein was not secreted and was instead aggregated in endoplasmic reticulum-derived vesicles. Cotransfection studies suggested that the R494X mutant could interact with wildtype protein, potentially with a dominant-negative effect. Using a CRISPR/Cas9 genome-editing approach, the authors generated a mouse line carrying the R494X mutation and observed no live homozygotes after embryonic day (E) 12.5, confirming that the R494X is functionally null. Heterozygotes were born normally, with a normal Schlemm canal, indicating that sufficient ANGPT/TEK signaling was present to allow vascular development, consistent with a minimal or absent dominant-negative effect. Heterozygotes carrying a floxed Angpt1 allele that was excised at E16.5 survived and exhibited a hypomorphic Schlemm canal, demonstrating that the R494X mutant cannot replace the wildtype protein in Schlemm canal development. Regarding the nonpenetrance observed in 2 of the PCG families, the authors noted that interindividual variability has been reported in nonsense-mediated decay efficiency, which might result in variable penetrance of disease.
In 4 affected women from a 3-generation Italian family with hereditary angioedema-5 (HAE5; 619361), Bafunno et al. (2018) identified a heterozygous c.807G-T transversion (c.807G-T, NM_001146.3) in exon 2 of the ANGPT1 gene, resulting in an ala119-to-ser (A119S) substitution at a conserved reside important for multimerization. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the 1000 Genomes Project or Exome Sequencing Project databases, but was found at a low frequency (8.2 x 10(-6)) in the ExAC database. Patient plasma showed normal levels of ANGPT1, but there was a reduction of multimeric forms compared to wildtype. The mutant protein also showed decreased binding to its membrane receptor TIE2 (600221). Similar results were obtained by expression of the mutation in HEK293 cells. Bafunno et al. (2018) hypothesized that the altered ANGPT1 function affects bradykinin-mediated endothelial permeability.
Using an in vitro model of an endothelial cell barrier, d'Apolito et al. (2019) found that, in contrast to wildtype ANGPT1, mutant A119S ANGPT1 failed to form proper cell-cell adhesions in the presence of VEGF or bradykinin, which induce vascular permeability. Presence of the mutation was associated with decreased expression of VE-cadherin (CDH5; 601120) at the cell membrane, decreased beta-catenin (CTNNB1; 116806) expression, and an impaired ability to block the formation of F-actin stress fibers that affect endothelial barrier permeability. D'Apolito et al. (2019) concluded that the mutation reduces the ability of ANGPT1 to counteract endothelial permeability induced by VEGF and bradykinin, resulting in vascular leakage. The findings were consistent with ANGPT1 haploinsufficiency.
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