Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activin receptor-like kinase 1 gene (ALK-1) is the second locus for the autosomal dominant vascular disease hereditary hemorrhagic telangiectasia (HHT). In this paper we present the genomic structure of the ALK-1 gene, a type I serine-threonine kinase receptor expressed predominantly in endothelial cells. The coding region is contained within nine exons, spanning < 15 kb of genomic DNA. All introns follow the GT-AG rule, except for intron 6, which has a TAG/gcaag 5' splice junction. The positions of introns in the intracellular domain are almost identical to those of the mouse serine-threonine kinase receptor TSK-7L. By sequencing ALK-1 from genomic DNA, mutations were found in six of six families with HHT either shown to link to chromosome 12q13 or in which linkage of HHT to chromosome 9q33 had been excluded. Mutations were also found in three of six patients from families in which available linkage data were insufficient to allow certainty with regard to the locus involved. The high rate of detection of mutations by genomic sequencing of ALK-1 suggests that this will be a useful diagnostic test for HHT2, particularly where preliminary linkage to chromosome 12q13 can be established. In two cases in which premature termination codons were found in genomic DNA, the mutant mRNA was either not present or present at barely detectable levels. These data suggest that mutations in ALK-1 are functionally null alleles.
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PMID:The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. 924 85

Endoglin (CD105), a component of the TGF-beta 1 receptor complex, is the target gene for the dominantly inherited vascular disorder hereditary hemorrhagic telangiectasia type 1 (HHT1). We have identified a novel endoglin splice site mutation, leading to an in-frame deletion of exon 3, in a new-born from a family with HHT. Expression of normal and mutant endoglin proteins was analyzed in umbilical vein endothelial cells from this 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 only detectable by metabolic labeling, as an intracellular homodimer of 130 kD. In monocytes from three clinically affected HHT1 patients, with known mutations creating premature stop codons in exons 8 and 10, surface endoglin was also reduced by half and no mutant was detected. Overexpression into COS-1 cells of endoglin cDNA truncated in exons 7 and 11, revealed their intracellular expression, inability to be secreted and to form heterodimers at the cell surface. These results indicate that mutated forms of endoglin are transiently expressed intracellularly and not likely to act as dominant negative proteins, as proposed previously. A reduction in the level of functional endoglin is thus involved in the generation of HHT1, and associated arteriovenous malformations.
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PMID:Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative. 936 72

Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited vascular disorder that is heterogeneous in terms of age of onset and clinical manifestations. Endoglin is the gene mutated in HHT1, which is associated with a higher prevalence of pulmonary arteriovenous malformations than HHT2, where ALK-1 is the mutated gene. Endoglin is constitutively expressed on endothelial cells and inducible on peripheral blood activated monocytes so that protein levels can be measured by metabolic labeling and immunoprecipitation. We report the analysis of umbilical vein endothelial cells in 28 newborns from 24 families with a clinical diagnosis of HHT. Reduced levels of endoglin were observed in umbilical vein endothelial cells in 15/28 subjects and in activated monocytes of all clinically affected relatives tested, suggesting that these individuals had HHT1. No mutant protein was expressed at the cell surface in any of these cases, and a transient intracellular species was seen in samples of only two families, supporting a haploinsufficiency model. Quantitative multiplex PCR fragment analysis was established for the endoglin gene and revealed six mutations that were confirmed by automated DNA sequencing. An additional 10 mutations were identified in newborns by sequencing all exons. Of the 16 mutations, 10 were novel, three had been independently identified in related families, and three were previously known. Our data confirm that endoglin levels correlate with the presence or absence of mutation in HHT1 families, allowing the early identification of affected newborns that should be screened clinically to avoid serious complications of this disorder, such as cerebral arteriovenous malformations.
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PMID:Identification of hereditary hemorrhagic telangiectasia type 1 in newborns by protein expression and mutation analysis of endoglin. 1062 79

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by dilated vessels and arteriovenous malformations. Phenotypic heterogeneity, such as age of onset, severity of disease and organ involvement, is explained in part by two genes being mutated, endoglin (HHT1) and ALK-1 (HHT2). Haploinsufficiency is the mechanism responsible for HHT. This implies that position and type of mutations cannot explain heterogeneity, because mutant proteins are not expressed at the cell surface and consequently cannot interfere with normal function. Based on this model, we generated mice expressing only one allele of endoglin, but in two different inbred strains, 129/Ola and C57BL/6. Phenotypic heterogeneity was also observed among the HHT mice and was very dependent on the genetic background. Our data strongly suggest that additional genes, contributed by the 129/Ola strain, are responsible for the vascular anomalies associated with HHT. The murine model is faithful to the human disease and should allow us to identify the modifier genes of HHT as well as to test potential therapeutic interventions.
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PMID:Endoglin-deficient mice, a unique model to study hereditary hemorrhagic telangiectasia. 1134 67

Hereditary haemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterised by epistaxis, telangiectases, and visceral manifestations. The two known disease types, HHT1 and HHT2, are caused by mutations in the endoglin (ENG) and ALK-1 genes, respectively. A higher frequency of pulmonary arteriovenous malformations (AVMs) has been reported for HHT1 while HHT2 is thought to be associated with a lower penetrance and milder disease manifestations. In this study, we present 10 families with an ALK-1 genotype. Visceral manifestations were detected in 24 (26%) of the 93 HHT2 patients from nine of the families and included gastrointestinal bleeding (14%), intrahepatic shunts (6%), and AVMs in the lung (4%) and brain (3%). Gastrointestinal bleeding, the most frequent visceral manifestation, was reported in six of the 10 families, mostly in patients over the age of 50. These patients also had frequent epistaxis and suffered from anaemia, often requiring blood transfusions. The identification of ALK-1 mutations in subjects with a suspected diagnosis and without clinical signs of HHT argue in favour of a molecular diagnosis. We also analysed the data published on 44 families with HHT2 and conclude that visceral manifestations occur in 26 of these families and affect 30% of HHT2 patients. This is considered an underestimate given incomplete and variable screening for lung, brain, and/or liver involvement in different clinical centres. These findings, however, stress the need for an early diagnosis of HHT that can be useful for the early control of associated visceral involvement.
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PMID:Visceral manifestations in hereditary haemorrhagic telangiectasia type 2. 1284 19

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM). Two genes are linked to HHT: endoglin (ENG) in HHT1 and activin receptor-like kinase 1 (ACVRL1; ALK1) in HHT2. Although both genes are involved in the transforming growth factor beta signaling pathways, the pathogenetic mechanisms for HHT remain elusive. It was shown that mutations in the Alk1 gene in mice and zebrafish resulted in an embryonic lethal phenotype due to severe dilation of blood vessels. We created a novel null mutant mouse line for Alk1 (Alk1lacZ) by replacing its exons, including the one that encodes the transmembrane domain, with the beta-galactosidase gene. Using Alk1lacZ mice, we show that Alk1 is predominantly expressed in developing arterial endothelium. Alk1 expression is greatly diminished in adult arteries, but is induced in preexisting feeding arteries and newly forming arterial vessels during wound healing and tumor angiogenesis. We also show that hemodynamic changes, which require vascular remodeling, may regulate Alk1 expression. Our studies suggest the role of Alk1 signaling in arterialization and remodeling of arteries. Contrary to the current view of HHT as venous disease, our findings suggest that the arterioles rather than the venules are the primary vessels affected by the loss of an Alk1 allele, and that blood vessels with reduction in Alk1 expression may harbor defects in responding to demands for vascular remodeling.
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PMID:Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. 1297 Jan 15

Hereditary hemorrhagic telangiectasia (HHT, Rendu-Osler-Weber disease) is a vascular disorder with dominant autosomal transmission characterised usually by multiple mucocutaneous and visceral abnormalities. Neurological manifestations due to the primary involvement of spinal cord by vascular malformations are rare. We present a young man with HHT associated with a central nervous system arteriovenous malformation and a giant perimedullary fistula, that was manifested as progressive myelopathy. The diagnosis was made coupling magnetic resonance imaging to selective spinal arteriography. The therapeutic option was endovascular treatment by mechanically detachable coils which resulted in full exclusion of the fistula with full improvement of symptoms. During follow-up a stable clinical and morphological outcome was achieved. Clinical manifestations in HHT, with emphasis on neurological symptoms, are reviewed as well as the therapeutic options to deal with giant perimedullary fistula.
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PMID:Giant spinal perimedullary fistula in hereditary haemorrhagic telangiectasia: diagnosis, endovascular treatment and review of the literature. 1455 3

Activin receptor-like kinase 1 (Acvrl1; Alk1) is a type I receptor for transforming growth factor-beta (TGF-beta). ALK1 plays a pivotal role in vascular development and is involved in the development of hereditary hemorrhagic telangiectasia 2 (HHT2), a dominantly inherited vascular disorder, and pulmonary hypertension. We have previously shown that Alk1 is expressed predominantly in arterial endothelial cells (ECs). Despite recent discoveries of a number of artery-specific genes, the regulatory elements of these genes have not been characterized. To investigate the cis-acting elements essential for the artery-specific Alk1 expression, we have generated a series of transgenic constructs with various lengths and regions of Alk1 genomic fragments connected to a LacZ reporter gene, and analyzed the reporter gene expression in transgenic mice. We found that a 9.2-kb genomic fragment, which includes 2.7-kb promoter region and the entire intron 2, is sufficient to drive arterial endothelium-specific expression. The defined regulatory region, as well as the transgenic mouse lines, would be invaluable resources in studying the mechanisms underlying angiogenesis, arteriogenesis, and vascular disorders, such as HHT and pulmonary hypertension. The full text of this article is available online at http://circres.ahajournals.org.
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PMID:Isolation of a regulatory region of activin receptor-like kinase 1 gene sufficient for arterial endothelium-specific expression. 1505 37

Hereditary Hemorrhagic telangiectasia is an autosomal dominant vascular disorder with high penetrance and variable expressivity. Most cases are caused by mutations in the endoglin gene on chromosome 9 (HHT type 1) or the activin receptor-like kinase 1 gene on chromosome 12 (HHT type 2). HHT is characterized by mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs). Neurological complications occur in 8 to 10% of the patients. Brain ischemia or abscess are often associated with pulmonary arteriovenous fistula. Cerebral or spinal arteriovenous malformations are frequent but have a lower risk of haemorrhage than sporadic AVMs and routine screening should not be practiced in adult patients. Routine screening should be discussed for children with a familial history of cerebral haemorrhage and/or HHT type 1.
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PMID:[Neuroimaging of hereditary hemorrhagic telangiectasia]. 1613 98

Passive smoking has been demonstrated to exert a variety of deleterious effects eventually resulting in vascular damage. Isoprostanes, a reliable marker of in vivo oxidation injury, have been shown to increase in active cigarette smoking. Data for passive smoking are lacking. We were examining the isoprostane 8-epi-PGF2alpha in 12 smokers and non-smokers exposed daily to passive cigarette smoke for 12 days. Plasma samples stored at liquid nitrogen from people having been examined earlier were used. Prevalues of 8-epi-PGF2alpha are higher in cigarette smokers. Exposure to passive smoking causes a significant increase in 8-epi-PGF2alpha in non-smokers, while in smokers there is only a trendwise increase. After repeated passive smoke exposure, 8-epi-PGF2alpha in non-smokers approaches the respective values of smokers. There is a significant correlation of 8-epi-PGF2alpha to the thromboxane (plasma, serum, conversion from exogenous precursor, 11-dehydro-TXB2) parameters (MDA, HHT- conversion) examined in these patients before. The findings document a significant temporary increase in in vivo oxidation injury due to passive smoke favouring development and/or progression of vascular disease.
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PMID:Passive cigarette smoking increases isoprostane formation. 1616 64


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