Alternative titles; symbols
HGNC Approved Gene Symbol: ENG
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): 9:127,815,016-127,854,658 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.11 | Telangiectasia, hereditary hemorrhagic, type 1 | 187300 | Autosomal dominant | 3 |
Endoglin (ENG), also called CD105, is a homodimeric membrane glycoprotein primarily associated with human vascular endothelium. It is also found on bone marrow proerythroblasts, activated monocytes, and lymphoblasts in childhood leukemia. Endoglin is a component of the transforming growth factor-beta (TGFB) receptor complex and binds TGFB1 (190180) with high affinity (Rius et al., 1998).
Gougos and Letarte (1990) isolated a cDNA encoding ENG lacking a leader sequence from an endothelial cell cDNA library. By screening a leukemia cell cDNA library, Bellon et al. (1993) obtained full-length cDNAs encoding 2 variants of ENG. Both contain a 25-amino acid leader peptide, followed by 561 residues in the extracellular portion and a 25-amino acid transmembrane sequence. However, the long variant has a 47-amino acid cytoplasmic tail, while the tail of the short variant contains only 14 residues. Flow cytometric and immunoprecipitation analyses indicated high expression of both the 160- and 170-kD disulfide-linked homodimer ENG variants at the cell surface. RT-PCR analysis detected expression of both variants on activated monocytes, endothelial cells, and placenta, with the long form being predominant.
Bellon et al. (1993) found that both isoforms of ENG could bind TGFB1.
Rius et al. (1998) cloned and characterized the promoter region of the ENG gene. They showed that the endoglin promoter exhibits inducibility in the presence of TGFB1, suggesting possible therapeutic treatments in HHT1 (187300) patients, in which the expression level of the normal endoglin allele might not reach the threshold required for its function.
Grisanti et al. (2004) analyzed endoglin expression in choroidal neovascular membranes (CNVMs) surgically excised from eyes with age-related macular degeneration (ARMD; see 153800). Endoglin expression was increased in the endothelial cells of CNVMs but was rarely associated with a concomitant expression of the proliferation marker Ki-67 (176741). The authors concluded that the elevated expression of endoglin in the surgically excised CNVMs suggested a persisting postmitotic activation in an advanced stage of neovascular tissue.
Hereditary hemorrhagic telangiectasia (see 187300) and cerebral cavernous malformations (see 116860) are disorders involving disruption of normal vascular morphogenesis. The autosomal dominant mode of inheritance in both of these disorders suggested to Marchuk et al. (2003) that their underlying genes might regulate critical aspects of vascular morphogenesis. The authors summarized the roles of these genes, endoglin, KRIT1 (604214), and ALK1 (ACVRL1; 601284), in the genetic control of angiogenesis.
Lebrin et al. (2004) found that mouse endothelial cells lacking endoglin did not grow because Tgfb/Alk1 signaling was reduced and Tgfb/Alk5 (190181) signaling was increased. Surviving cells adapted to the imbalance and proliferated by downregulating Alk5 expression. Lebrin et al. (2004) concluded that endoglin has a role in the balance of ALK1 and ALK5 signaling to regulate endothelial cell proliferation.
GIPC1 (605072) is a scaffolding protein that regulates cell surface receptor expression and trafficking. Using predominantly embryonic mouse endothelial cell lines, Lee et al. (2008) showed that endoglin and Gipc interacted directly. The interaction enhanced TGF-beta-1-induced phosphorylation of Smad1 (601595)/Smad5 (603110)/Smad8 (SMAD9; 603295), increased a Smad1/Smad5/Smad8-responsive promoter, and inhibited endothelial cell migration.
Chen et al. (2009) found increased levels of soluble endoglin in vascular surgical specimens from 33 patients with arteriovenous malformations of the brain (BAVM; 108010) compared to similar specimens from 8 epileptic patients. However, there was no difference in expression of membrane-bound endoglin and no difference in plasma soluble endoglin between BAVM patients and controls. Transduction of soluble endoglin in mouse brain resulted in the formation of abnormal and dysplastic capillary structures, and was associated with increased levels of matrix metalloproteinase activity and oxidative radicals. Chen et al. (2009) suggested that soluble endoglin may play a role in the formation of sporadic BAVM by acting as a decoy receptor, resulting in inhibition of TGF-beta signaling and functional haploinsufficiency of ENG, as observed in patients with HHT1.
Muenzner et al. (2010) found that CEA (114890)-binding bacteria colonized the urogenital tract of CEA transgenic mice, but not of wildtype mice, by suppressing exfoliation of mucosal cells. CEA binding triggered de novo expression of the transforming growth factor receptor CD105, changing focal adhesion composition and activating beta-1 integrins (135630). Muenzner et al. (2010) concluded that this manipulation of integrin inside-out signaling promotes efficient mucosal colonization and represents a potential target to prevent or cure bacterial infections.
Wang et al. (2013) identified upregulation of Lrg1 (611289) in the transcriptome of retinal microvessels isolated from mouse models of retinal disease that exhibit vascular pathology. The authors showed that in the presence of transforming growth factor-beta-1 (TGFB1; 190180), Lrg1 is mitogenic to endothelial cells and promotes angiogenesis. Mice lacking Lrg1 developed a mild retinal vascular phenotype but exhibited a significant reduction in pathologic ocular angiogenesis. Lrg1 bound directly to the Tgf-beta accessory receptor endoglin, which, in the presence of TGF-beta-1, resulted in promotion of the proangiogenic Smad1/5/8 signaling pathway. Lrg1 antibody blockade inhibited this switch and attenuated angiogenesis. Wang et al. (2013) concluded that these studies revealed that LRG1 is a regulator of angiogenesis that mediates its effect by modulating TGF-beta signaling.
McAllister et al. (1994) concluded that the coding region of the ENG gene contains 14 exons. They thought it likely that there are additional exons.
By Southern blot analysis of DNA from human-hamster somatic cell hybrids, Fernandez-Ruiz et al. (1993) mapped the ENG gene to human chromosome 9. By fluorescence in situ hybridization, they regionalized the assignment to 9q34-qter, distal to the breakpoint of the Philadelphia chromosome. The mouse endoglin locus is genetically inseparable from the adenylate kinase-1 locus (Pilz et al., 1994). Thus, the ENG gene is probably located in the 9q34.1 region in the human. Qureshi et al. (1995) mapped the mouse ENG homolog to chromosome 2, near the nebulin locus (161650).
In a panel of 68 DNA samples from probands of unrelated hereditary hemorrhagic telangiectasia (see HHT1; 187300) families, most of whom were members of kindreds with pulmonary arteriovenous malformations (PAVMs), McAllister et al. (1994) identified mutations in the ENG gene in 3 affected individuals.
Shovlin et al. (1997) identified 7 novel mutations in the ENG gene in 8 families. Two of the mutations (a termination codon in exon 4 and a large genomic deletion extending 3-prime of intron 8) did not produce a stable ENG transcript in lymphocytes. Five other mutations (2 donor splice site mutations (e.g., 131195.0004) and 3 deletions) produced altered mRNAs that were predicted to encode markedly truncated ENG proteins. These data suggested that the molecular mechanism by which ENG mutations cause HHT is haploinsufficiency. Furthermore, because the clinical manifestation of disease in these 8 families was similar, Shovlin et al. (1997) hypothesized that phenotypic variation of HHT is not related to a particular ENG mutation. They found that 41% (23 of 56) of HHT patients with ENG mutations had pulmonary arteriovenous malformations, whereas a significantly smaller fraction, 14% (5 of 35), of HHT patients in whom linkage analyses indicated non-ENG mutations had PAVMs (P less than 0.01).
In a newborn from a family with HHT, Pece et al. (1997) identified a novel endoglin splice site mutation (131195.0005) that resulted in skipping of exon 3 and the expression of a mutant protein missing 47 amino acids but with an intact transmembrane region. This mutant protein was considered particularly suited for testing the dominant-negative model as it is more likely to be expressed at the cell surface than truncated ones. However, it was detectable only by metabolic labeling, did not form heterodimers with normal endoglin, and did not reach the cell surface. In activated monocytes from 3 patients with known truncations, no mutant protein could be detected. However, when cDNA corresponding to 2 other HHT1 endoglin truncations were overexpressed in COS-1 cells, mutant proteins could be detected intracellularly, were not secreted, and did not form heterodimers with wildtype endoglin. Thus, Pece et al. (1997) concluded that mutant endoglin in HHT patients appears to be only transiently expressed and not to represent a dominant negative. The data strongly suggested that a reduced level of functional endoglin leads to the abnormalities seen in HHT1 patients. In these studies, expression of normal and mutant endoglin proteins was analyzed in umbilical vein endothelial cells from the baby and in activated monocytes from the affected father. In both samples, only normal dimeric endoglin (160 kD) was observed at the cell surface, at 50% of control levels. Despite an intact transmembrane region, mutant protein was detectable only by metabolic labeling, as an intracellular homodimer of 130 kD.
Gallione et al. (1998) described 11 novel ENG mutations in HHT kindreds, which included missense and splice site mutations. In 2 unrelated families, they identified a T-to-C transition in the ATG initiation codon, which converted the initiator methionine to threonine. Non-ATG codons can initiate at 3 to 5% of normal translation levels when flanked by specific consensus sequences (Kozak, 1989). However, the sequence context of the specific mutation in the 2 HHT families did not fit the consensus for even such reduced initiation. The first potential in-frame initiation codon was within exon 5. If protein synthesis was initiated at this position, the product would lack the signal peptide for proper membrane trafficking, as well as 30% of the N-terminal residues. This initiation codon mutation appeared to be a classic null allele that eliminated the translation of the endoglin protein.
Pece-Barbara et al. (1999) stated that to that date 29 different mutations had been reported in HHT1 in the endoglin gene and 18 distinct mutations had been described for the ALK1 gene (601284), which underlies type 2 hereditary hemorrhagic telangiectasia (HHT2; 600376).
Although a dominant-negative model of endoglin dysfunction was initially proposed for HHT1, Pece et al. (1997) observed a mutant protein (131195.0005) that was transiently expressed intracellularly both in monocytes from an HHT1 patient and in human umbilical vein endothelial cells (HUVECs) from the child of the patient. As the cell surface-expressed protein was still able to associate with the TGF-beta receptor complex, this indicated that it is the reduction in the level of surface endoglin, rather than interference by mutant protein, that is involved in the generation of HHT1. The description of 3 null mutations where mRNA transcripts were undetectable again suggested that endoglin haploinsufficiency is the molecular basis for HHT1. The observation that every HHT1 family so far studied was found to have a distinct mutation and that mutations of all types are distributed throughout the gene was again consistent with a haploinsufficiency model. Pece-Barbara et al. (1999) studied 4 missense mutations and found that none was significantly expressed at the surface of COS-1 transfectants. Thus, although these 4 HHT1 missense mutations led to transient intracellular species, they cannot interfere with normal endoglin function.
To determine whether mechanisms other than haploinsufficiency might be involved in HHT1, Lux et al. (2000) investigated 8 different mutations in the ENG gene. Missense mutants were expressed but apparently misfolded, and most showed no cell surface expression. When coexpressed with wildtype endoglin, missense mutants were able to dimerize with normal endoglin protein and were transported to the cell surface. The protein product of one truncation mutation was unable to dimerize with normal endoglin, and likely acts through haploinsufficiency. On the contrary, the delta-GC frameshift mutation (131195.0003) was able to dimerize with normal endoglin, and likely acts in a dominant-negative fashion by interfering with protein processing or cell surface expression. Thus, the authors concluded that either dominant-negative protein interactions or haploinsufficiency can cause HHT1.
To maximize the detection of potential mutant proteins, Paquet et al. (2001) utilized pulse-chase experiments to analyze the expression of large truncation mutations and missense mutations in cells from HHT1 patients with 13 unique mutations. All HHT1 mutants analyzed, although expressed to various degrees in COS-1 cells, were either undetectable, present at low levels as transient intracellular forms, or expressed as partially glycosylated precursors in endogenous cells. The mutants did not form heterodimers with normal endoglin and did not interfere with its normal trafficking to the cell surface, further supporting the haploinsufficiency model.
In COS-1 transfected cells, Abdalla et al. (2000) determined that ALK1 was found in the TGFB1 and -B3 (190230) receptor complexes in association with endoglin and TGFBR2 (190182), but not in activin (see 147290) receptor complexes containing endoglin. In HUVEC, ALK1 was not detectable in TGFB1 or -B3 receptor complexes. However, in the absence of ligand, ALK1 and endoglin interactions were observed by immunoprecipitation/Western blot in HUVEC from normal as well as HHT1 and HHT2 patients. The authors hypothesized that a transient association between ALK1 and endoglin is required at a critical level to ensure vessel wall integrity.
Cymerman et al. (2003) optimized a quantitative multiplex PCR (QMPCR) analysis to efficiently detect deletions and insertions in the ENG gene in HHT1 patients from 18 families. They reported 17 novel mutations, of which 6 were detected by QMPCR. Review of 80 HHT1 families (62 previously reported and the 18 described) indicated that 10% would not have been resolved by sequencing and that an additional 25% could be revealed by QMPCR performed before sequencing. Thus the use of QMPCR can accelerate genetic screening for HHT1 and resolve mutations affecting whole exons.
Lastella et al. (2003) detected 4 novel and 1 previously reported mutation in the ENG gene in Italian patients with HHT.
In 160 unrelated cases of HHT, Lesca et al. (2004) screened the coding sequences of the ENG and ALK1 genes. Germline mutations were identified in 100 patients (62.5%): 36 of the mutations were in ENG and 64 were in ALK1.
In 7 Danish HHT families, Brusgaard et al. (2004) identified a novel nonsense mutation (131195.0009) in the ENG gene, which they characterized as a founder mutation.
Abdalla and Letarte (2006) tabulated the known ENG mutations identified in hereditary hemorrhagic telangiectasia.
Bayrak-Toydemir et al. (2006) identified mutations in 26 (76%) of 34 kindreds with HHT. Fourteen (54%) mutations were in the ENG gene, consistent with HHT1, and 12 (46%) were in the ACVRL1 gene, consistent with HHT2.
Wehner et al. (2006) identified mutations in 32 (62.7%) of 51 unrelated German patients with HHT. Among these mutations, 11 of 13 ENG mutations and 12 of 17 ACVRL1 mutations were not previously reported in the literature. Analysis of genotype/phenotype correlations was consistent with a more common frequency of PAVMs in patients with ENG mutations (HHT1).
Sweet et al. (2005) sequenced the ENG gene in 14 patients with juvenile polyposis syndrome (JPS; 174900) who were negative for mutation in the 2 known JPS genes, SMAD4 (600993) and BMPR1A (601299), and identified germline missense mutations in the ENG gene in 2 patients, respectively. The mutations were not found in 105 North American controls. In 3 of 31 patients with JPS who were negative for mutations in the SMAD4 and BMPR1A genes, Howe et al. (2007) identified 2 different nonsynonymous substitutions that had been previously identified as polymorphisms in patients with HTT. Howe et al. (2007) stated that their findings did not confirm the suggestion that the ENG gene predisposes for JPS.
In a German woman with clinical features of HHT and negative direct sequencing results, Shoukier et al. (2008) identified a deletion of exon 4 of the ENG gene using quantitative real-time polymerase chain reaction (qRT-PCR) and confirmed by multiplex ligation-dependent probe amplification (MLPA).
Li et al. (1999) generated mice deficient for endoglin using homologous recombination. Eng +/- mice had normal life expectancy, fertility, and gross appearance. Eng -/- mice died by embryonic day 11.5. At embryonic day 10.5, Eng -/- mice were 3 times smaller than Eng +/+ mice and had fewer somites. The Eng -/- embryos exhibited an absence of vascular organization and the presence of multiple pockets of red blood cells on the surface of the yolk sac. Epithelial marker expression was not disrupted in Eng -/- mice. There was persistence of an immature perineural vascular plexus, indicating a failure of endothelial remodeling in Eng -/- embryos. At embryonic day 10.5, the cardiac tube did not complete rotation and was associated with a serosanguinous pericardial effusion. By embryonic day 10.5, the major vessels including the dorsal aortae, intersomitic vessels, branchial arches, and carotid arteries were atretic and disorganized in Eng -/- embryos. There was also poor vascular smooth muscle cell formation at both embryonic days 9.5 and 10.5. These vascular smooth muscle cell abnormalities preceded the differences in endothelial organization. In contrast to mice lacking TGF-beta, vasculogenesis was unaffected. Li et al. (1999) concluded that their results demonstrated that endoglin is essential for angiogenesis and suggest a pathogenic mechanism for HHT1.
Bourdeau et al. (1999) likewise generated mice lacking 1 or both copies of the endoglin gene. Endoglin null embryos died at gestational day 10.0-10.5 due to defects in vessel and heart development. Vessel formation appeared normal until hemorrhage occurred in yolk sacs and embryos. The primitive vascular plexus of the yolk sac failed to mature into defined vessels, and vascular channels dilated and ruptured. Internal bleeding was seen in the peritoneal cavity, implying fragile vessels. Heart development was arrested at day 9.0, and the atrioventricular canal endocardium failed to undergo mesenchymal transformation and cushion-tissue formation. The data suggested that endoglin is critical for both angiogenesis and heart valve formation. Some heterozygotes showed signs of HHT, such as telangiectases or recurrent nosebleeds. In this murine model of HHT, it appeared that epigenetic factors and modifier genes, some of which are present in the 129/Ola strain, which shows expressing heterozygotes, contribute to disease heterogeneity.
Lebrin et al. (2010) showed that treatment of Eng +/- with thalidomide normalized inappropriate vessel formation and promoted pericyte and mural cell activation and vessel maturation via increased expression of Pdgfb (190040). In vitro studies of mouse tissue showed that thalidomide stimulated the recruitment of mural cells to the vessel branches, resulting in a stabilization of blood vessels and a rescue of vessel wall defects. Treatment reduced nosebleed frequency in 6 of 7 humans with HHT, and reduced the duration of nosebleeds in 3 of 4 for whom data were available.
In a patient with hereditary hemorrhagic telangiectasia (HHT1; 187300), McAllister et al. (1994) found a C-to-G transition at nucleotide position 831 in the ENG gene, resulting in conversion of tyrosine-277 to a termination codon. The truncated protein resulting from this mutation would comprise only half of the extracellular domain and lack the membrane-spanning and cytoplasmic domains.
In affected members of a family with hereditary hemorrhagic telangiectasia (HHT1; 187300), McAllister et al. (1994) found deletion of 39 nucleotides (882 to 920) in exon 7 of the ENG gene, removing 13 amino acids from the protein and altering the first amino acid (position 307) in a potential N-linked glycosylation site. The mutation segregated only with affected members of the 3-generation family.
In affected members of a family with hereditary hemorrhagic telangiectasia (HHT1; 187300), McAllister et al. (1994) found a 2-bp deletion (nucleotides 1553 and 1554) in exon 11 of the ENG gene that created a MaeIII restriction site and caused a frameshift with a premature termination after an additional 7 amino acids. The predicted truncated protein would lack the membrane-spanning and cytoplasmic domains of endoglin.
One of 7 novel mutations in the ENG gene found by Shovlin et al. (1997) in patients with hereditary hemorrhagic telangiectasia-1 (HHT1; 187300) was a deletion of exon 3 due to an A-to-G transition at position 4 of the donor splice site of intron 3.
In a patient with hereditary hemorrhagic telangiectasia-1 (HHT1; 187300), Pece et al. (1997) detected a splice site mutation of the ENG gene, resulting in in-frame deletion of exon 3 from the transcript and a truncated polypeptide.
In 2 unrelated families with hereditary hemorrhagic telangiectasia-1 (HHT1; 187300), Gallione et al. (1998) identified a missense mutation of the initiation codon of the ENG gene. A T-to-C transition converted ATG (met) to ACG (thr). Since flanking sequences did not satisfy the consensus sequences found by Kozak (1989) to permit initiation from non-ATG codons and the first potential in-frame initiation codon was within exon 5, Gallione et al. (1998) predicted that this would function as a classic null mutation.
In the Leeward Islands of the Netherlands Antilles where the prevalence of hereditary hemorrhagic telangiectasia (HHT1; 187300) is perhaps the highest of any geographic region, Gallione et al. (2000) found that 1 of 2 common mutations was a missense mutation in exon 9a of the ENG gene: a G-to-T transversion at nucleotide 1238, resulting in a gly413-to-val substitution.
In 7 of 10 families in the Netherlands Antilles with hereditary hemorrhagic telangiectasia (HHT1; 187300), Gallione et al. (2000) found a splice site mutation in the ENG gene: a G-to-A transition at position +1 of intron 1.
In 7 of 25 Danish families with hereditary hemorrhagic telangiectasia (HHT1; 187300), Brusgaard et al. (2004) identified a 360C-A transversion in exon 3 of the ENG gene, resulting in a tyr120-to-ter (Y120X) substitution. Brusgaard et al. (2004) thought the Y120X founder mutation may have been introduced around 350 years earlier.
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