Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease

Abdalla, S A

doi:10.1136/jmg.2005.030833

Cited by 334 publications

(326 citation statements)

References 122 publications

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“…12 Dominant negative mutations in endoglin can be generated, but may cause different phenotypes; for example, truncated soluble endoglin is associated with the non-HHT phenotype of pre-eclampsia. 39 The genes mutated in HHT encode proteins involved in TGF-b superfamily signalling; perturbation of these signalling pathways is therefore implicated in the pathogenesis of HHT.…”

Section: Biology Of the Diseasementioning

confidence: 99%

“…Heterozygous mice develop variable, but more HHT-specific, features including nosebleeds, telangiectasia, dilated vessels and AVMs. 12,41 Conditional LoxP knockout alleles have been generated for all three HHT genes and for ALK1, result in a model in which HHT-like vascular malformations occurred in a consistent and predictable manner. 44 These and other models are under active study.…”

Section: Biology Of the Diseasementioning

confidence: 99%

“…Asymptomatic screening and treatment programmes form major components of HHT management. Useful recent reviews include those by Abdalla et al, 12 BayrakToydemir et al, 13 Begbie et al 14 and by Sabba et al 15 Clinical overview HHT was first described as a familial disease characterised by anaemia, severe recurrent nosebleeds and gastrointestinal blood loss. 16,17 There was early recognition of HHT-affected individuals developing abnormal vascular structures at other sites, particularly AVMs of the pulmonary, 18 hepatic 19 and cerebral 20 circulations.…”

Section: Introductionmentioning

confidence: 99%

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Hereditary haemorrhagic telangiectasia: a clinical and scientific review

2009

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In association withHereditary haemorrhagic telangiectasia: a clinical and scientific reviewThe autosomal-dominant trait hereditary haemorrhagic telangiectasia (HHT) affects 1 in 5-8000 people. Genes mutated in HHT (most commonly for endoglin or activin receptor-like kinase (ALK1)) encode proteins that modulate transforming growth factor (TGF)-b superfamily signalling in vascular endothelial cells; mutations lead to the development of fragile telangiectatic vessels and arteriovenous malformations. In this article, we review the underlying molecular, cellular and circulatory pathobiology; explore HHT clinical and genetic diagnostic strategies; present detailed considerations regarding screening for asymptomatic visceral involvement; and provide overviews of management strategies.

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Section: Biology Of the Diseasementioning

confidence: 99%

Section: Biology Of the Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hereditary haemorrhagic telangiectasia: a clinical and scientific review

2009

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“…There is variability in the organs affected, even between individuals within families [81]. Three genes are causally related to HHT, i.e.…”

Section: Hereditary Hemorrhagic Telangiectasia (Hht)mentioning

confidence: 99%

TGF-β signaling in vascular biology and dysfunction

2008

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Transforming growth factor (TGF)-β family members are multifunctional cytokines that elicit their effects on cells, including endothelial and mural cells, via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. Knock-out mouse models for TGF-β family signaling pathway components have revealed their critical importance in proper yolk sac angiogenesis. Genetic studies in humans have linked mutations in these signaling components to specific cardiovascular syndromes such as hereditary hemorrhagic telangiectasia, primary pulmonary hypertension and Marfan syndrome. In this review, we present recent advances in our understanding of the role of TGF-β receptor signaling in vascular biology and disease, and discuss how this may be applied for therapy.

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“…1,2 The most common clinical symptoms of HHT are nosebleeds and mucocutaneous telangiectases. Telangiectasic lesions exhibit dilation of the vascular lumen, thinning of the vascular wall, and arteriovenous malformations (AVMs)-direct connections between arterioles and venules without intervening capillaries.…”

mentioning

confidence: 99%

Activin receptor-like kinase 1 is essential for placental vascular development in mice

Hong

Seki

2007

Laboratory Investigation

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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. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder occurring in one out of 10 000 people. 1,2 The most common clinical symptoms of HHT are nosebleeds and mucocutaneous telangiectases. Telangiectasic lesions exhibit dilation of the vascular lumen, thinning of the vascular wall, and arteriovenous malformations (AVMs)-direct connections between arterioles and venules without intervening capillaries. Large AVMs in the lungs, brain, liver, and gastrointestinal track of HHT patients can cause life-threatening complications. Genetic studies have revealed that heterozygous mutations in ENDOGLIN (ENG) or Activin receptor-like kinase 1 (ALK1; ACVRL1) cause HHT1 and HHT2, respectively. 3,4 Recent reports have shown that some SMAD4 mutations can also cause HHT. 5 ENG and ALK1 are, respectively, a type III and type I receptor for transforming growth factor-b (TGF-b) superfamily ligands. SMAD4 is a common mediator of all SMADdependent TGF-b family signaling. It is conceivable that HHT is caused by impairment of mediating a TGF-b family ligand common to ENG, ALK1, and SMAD4. Although TGFb1 and b3 have been considered the most likely ligands for ENG/ALK1 signaling, as both ENG and ALK1 interact with multiple TGF-b family ligands, the issue concerning the identity of the HHT-causing ligand for ENG/ALK1 remains unresolved. 6 Heterozygous Alk1-null mice develop an array of HHT-like vascular malformations. 7 As the frequency, time of onset, and location of vascular lesions in these mice are as unpredictable as in humans with HHT, the heterozyg...

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Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease

Cited by 334 publications

References 122 publications

Hereditary haemorrhagic telangiectasia: a clinical and scientific review

Hereditary haemorrhagic telangiectasia: a clinical and scientific review

TGF-β signaling in vascular biology and dysfunction

Activin receptor-like kinase 1 is essential for placental vascular development in mice

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