Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary arterial hypertension is a recognized clinical component of systemic autoimmune diseases, especially systemic sclerosis. Mutations in the bone morphogenetic protein receptor 2 gene reported in sporadic and familial primary pulmonary arterial hypertension have failed to be detected in patients with either scleroderma spectrum disease or underlying connective tissue diseases. Activin receptor-like kinase 1 (ALK-1) gene has recently been linked to the pathogenesis of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia, which has some resemblance with the CREST syndrome. The presence of mutations in the ALK-1 gene in ten patients with underlying connective tissue diseases was investigated.
 ...
PMID:Mutations of activin-receptor-like kinase 1 (ALK-1) are not found in patients with pulmonary hypertension and underlying connective tissue disease. 1694 Dec 3

Activin receptor-like kinase 1 (ALK1) is involved in the pathogenesis of hereditary hemorrhagic telangiectasia type II (HHT2) and pulmonary arterial hypertension. We have previously shown that Alk1 is predominantly expressed in the arterial endothelium and plays a pivotal role in the formation of embryonic blood vessels. At present, however, little is known about the precise expression pattern and function of ALK1 during extra-embryonic vascular development. Using previously generated lacZ reporter lines, we sought to examine the expression pattern and role of Alk1 during placental development in mice. Alk1 expression was restricted to endothelial cells of fetal vessels from the emergence of chorioallantoic fusion to the late gestational period, and no detectable Alk1 expression was observed in syncytiotrophoblasts or spongiotrophoblasts. Predominant arterial expression was observed in the umbilical and fetal placental vessels as well as in embryonic vessels. Morphological analysis of Alk1-null embryos indicates that Alk1 is essential for the development of distinct umbilical arteries and veins. The invasion of chorioallantoic mesoderm into the forming labyrinth layer was largely unaffected in the Alk1-null placenta, but chorioallantoic vessels appeared to be severely dilated and fused. Results from this study provide valuable information regarding the role of ALK1 in the development of placental vasculature as well as insights into the pathogenesis of HHT.
 ...
PMID:Activin receptor-like kinase 1 is essential for placental vascular development in mice. 1753 30

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is a genetic disorder with autosomal dominance and variable penetrance, characterized by epistaxis, telangiectasia and visceral manifestations of the disease. The estimated minimal prevalence is 1/10,000 inhabitants. The diagnosis is established on clinical criteria, and may be further confirmed by the identification of causative mutations in either the ENG or the ACVRL1 gene coding for endoglin and ALK1, respectively. Pulmonary vascular manifestations of HHT include pulmonary arteriovenous malformations (PAVMs; especially in patients with ENG mutations) and less frequently pulmonary hypertension (especially in patients with ACVRL1 mutations). In 15-33% of patients with HHT, PAVMs consist of abnormal communications between pulmonary arteries and pulmonary veins, causing right-to-left shunting, and thus, frequently hypoxemia and dyspnea on exertion, although PAVMs may remain asymptomatic and frequently undiagnosed unless complications occur. PAVMs result in severe and frequent complications often at a young age, which may reveal the diagnosis, e.g. transient ischemic attack and cerebral stroke (10-19% of patients), systemic severe infections and abscesses (including cerebral abscess in 5-19% of patients), and rarely massive hemoptysis or hemothorax. Infections in HHT are related to the right-to-left shunting that bypasses the pulmonary capillaries and facilitates the passage of septic or aseptic emboli into the systemic and especially cerebral circulation, and potentially to minor defects in innate immunity. Treatment of PAVMs based on transcatheter coil vaso-occlusion of the feeding artery significantly decreases right-to-left shunting, hypoxemia and dyspnea on exertion, and reduces the risk of systemic complications. Long-term follow-up is warranted after transcatheter vaso-occlusion of PAVMs due to frequent recanalization of treated PAVMs and development or growth of untreated PAVMs. Patients with HHT should be informed of the risk of PAVM and potentially severe complications occurring in heretofore asymptomatic subjects. All adult patients with HHT should be proposed systematic screening for PAVM, by contrast echocardiography (preceded by anteroposterior chest radiograph) or computed tomography of the chest. Pulmonary hypertension is rare in HHT, and may be due either to systemic arteriovenous shunting in the liver increasing cardiac output or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension. Pulmonary hypertension is detected by systematic examination of right cardiac cavities and tricuspid regurgitation flow at echocardiography, and the diagnosis is established by right heart catheterization.
 ...
PMID:Pulmonary vascular manifestations of hereditary hemorrhagic telangiectasia (rendu-osler disease). 1764 82

Arteriovenous malformations (AVMs) are direct connections between arteries and veins associated with loss of the intervening capillary bed. In the lungs, pulmonary AVMs can result in right to left shunts and severe cyanosis and dyspnoea. However, the cellular and molecular mechanisms underlying AVM formation are poorly understood. One important clue comes from the fact that pulmonary AVMs frequently occur in the familial disease hereditary haemorrhagic telangiectasia (HHT), which is associated with mutations in one of two receptors involved in transforming growth factor-beta family signalling, either endoglin (ENG) or activin receptor-like kinase 1 (ACVRL1, also known as ALK1). To elucidate the potential link between ENG or ACVRL1 deficiency and AVM formation in HHT, we performed a comprehensive study of Acvrl1 and Eng expression in wild-type and Eng-deficient (Eng+/-) mouse lungs using a combination of immunohistochemistry and RT-PCR from laser-microdissected arteries, veins and capillaries. We found that Eng and Acvrl1 have distinct expression profiles in the pulmonary vasculature and are only co-expressed in the distal (pre-capillary) arteries, distal veins and capillaries, consistent with the tendency for pulmonary AVMs to form in the distal pulmonary vessels in HHT. Downstream pSmad1/5/8 activity was found in the distal arteries and was specifically reduced in Eng+/- mice, consistent with previous in vitro data showing that Eng promotes Acvrl1-mediated Smad1/5/8 phosphorylation. Eng was more widely expressed than Acvrl1 in the lungs, as Eng alone was found in pulmonary veins, potentially explaining the increased frequency of AVMs in HHT1 patients. Furthermore, the association of ACVRL1 mutations with a second vascular disease, familial pulmonary artery hypertension, underlines the importance of ACVRL1 expression in the distal arteries that are affected in this disorder.
 ...
PMID:Endoglin and activin receptor-like-kinase 1 are co-expressed in the distal vessels of the lung: implications for two familial vascular dysplasias, HHT and PAH. 1901 42

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder caused by mutations in the ACVRL1, ENG, and SMAD4 genes. HHT is commonly characterised by small arteriovenous malformations (AVMs) known as telangiectasias of the skin, oral or gastrointestinal mucosa, as well as larger AVMs of solid organs (lungs, liver, brain). However, the manifestations of HHT are extremely variable. Two patients with no family history of HHT and strikingly different clinical presentations, who are mosaic for mutations in the ACVRL1 or ENG gene, are reported here. These cases represent the first report of mosaicism in patients clinically affected with classical HHT and pulmonary arterial hypertension, and suggest the need for awareness of mosaicism when performing clinical testing for this disorder.
 ...
PMID:Mosaic ACVRL1 and ENG mutations in hereditary haemorrhagic telangiectasia patients. 2137 82

Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding.
...
PMID:Genetics and genomics of pulmonary arterial hypertension. 2569 31

Mutations of the ACVRL1 gene are a cause of hereditary haemorrhagic telangiectasia (HHT) type 2. In this case report, we present a patient with isolated pulmonary arterio-venous malformations (PAVMs) without other diagnostic criteria for HHT and a novel mutation in exon 10 of the ACVRL1 gene. Other mutations in exon 10 of ACVRL1 have been linked to the development of pulmonary artery hypertension, but PAVMs are a rare manifestation of HHT associated with ACVRL1 mutations. A disrupted endothelial TGF-beta/BMP signaling cascade underlies the pathogenesis of HHT, but the exact mechanism of the disease remains unelucidated. In particular, the factors that influence the variable clinical presentation are not fully understood.
...
PMID:Pulmonary arterio-venous malformations in a patient with a novel mutation in exon 10 of the ACVRL1 gene. 2472 59

Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore; common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural-history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding. (J Am Coll Cardiol 2013;62:D13-21) a 2013 by the American College of Cardiology Foundation.
 ...
PMID:[Genetics and genomics of pulmonary arterial hypertension]. 2435 37

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited disorder characterised by vascular malformations in predominantly the brain, liver and lungs. Pulmonary hypertension (PH) is increasingly recognised as a severe complication of HHT. PH may be categorised into two distinct types in patients with HHT. Post-capillary PH most often results from a high pulmonary blood flow that accompanies the high cardiac output state associated with liver arteriovenous malformations. Less frequently, the HHT-related gene mutations in ENG or ACVRL1 appear to predispose patients with HHT to develop pre-capillary pulmonary arterial hypertension. Differentiation between both forms of PH by right heart catheterisation is essential, since both entities are associated with severe morbidity and mortality with different treatment options. Therefore all HHT patients should be referred to an HHT centre.
...
PMID:Pulmonary hypertension in hereditary haemorrhagic telangiectasia. 2601 55

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominantly inherited vascular-malformation syndrome associated with gene mutations including ENG, ACVRL1 and SMAD4 gene. Clinically indistinguishable HHT1 and HHT2 are caused by mutations in ENG and ACVRL1 gene, respectively. Generally, pulmonary arteriovenous malformations (PAVMs) and pulmonary arterial hypertension (PAH) are rare manifestations of HHT related to ACVRL1 gene mutations. We described a female patient with HHT2 whose clinical features included epistaxis, mucocutaneous telangiectases, systemic AVMs and PAH. She also suffered from severe iron deficiency anemia and recurrent heart failure. A genetic mutation analysis disclosed a missense mutation in exon 7 of ACVRL1 gene in this patient and her daughter. A nonsense mutation in exon 7 of ACVRL1 gene was detected in her brother and her niece. This case supports that PAVMs and PAH can be rare manifestations of HHT2 patients.
...
PMID:Heart failure and pulmonary arteriovenous malformations in a patient with hereditary hemorrhagic telangiectasia type 2. 2624 26


1 2 Next >>