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Hereditary Haemorrhagic Telangiectasia (HHT): genetic and molecular aspects
- Source :
- Current pharmaceutical design. 12(10)
- Publication Year :
- 2006
-
Abstract
- Hereditary Haemorrhagic Telangiectasia, or Rendu-Osler-Weber syndrome, is a rare autosomal dominant disorder involving the vascular system and is characterised by a highly variable expressivity and age-dependent penetrance. Diagnosis is based on the presence of at least three of four of the following symptoms: spontaneous epistaxis, cutaneous telangiectases, arteriovenous malformations in internal organs and familiarity. Recurrent complications are severe anaemia, stroke, portal and pulmonary hypertension. The peculiar characteristic of this disease is the diffusion of arteriovenous malformations, that is, localised abnormal arteriovenous connections affecting both microvasculature and large vessels. HHT is actually a heterogenous genetic disorder, divided into two clinically indistinguishable forms: HHT1 caused by mutations in endoglin gene mapping on chromosome 9q, and HHT2 caused by mutations in ALK1 located on chromosome 12q. Haploinsufficiency is the underlying mechanism for endoglin and most ALK1 mutations. Such mutations lead to a deficiency in angiogenesis, i.e. the sprouting of new vessels from pre-existing ones. To date, little is still known about the mechanism(s) responsible for lesion formation, development and slow growth. Current models focus on the role that TGF-beta superfamily members, a vast group of multifunctional cytokines, play in endothelial responses to angiogenic stimuli. As both genes seem to act in TGF-beta signal transduction pathways, SMAD proteins are also thought to be involved. There is no clear explanation accounting for the strong variability shown even among members of the same family despite the sharing of the same disease-causing mutation, and why lesions are spatially discrete.
- Subjects :
- Pathology
medicine.medical_specialty
Genotype
Angiogenesis
Activin Receptors, Type II
Receptors, Cell Surface
Smad Proteins
medicine.disease_cause
Antigens, CD
Drug Discovery
medicine
Humans
Pharmacology
Mutation
business.industry
Vascular disease
Genetic disorder
Hereditary haemorrhagic telangiectasia (HHT)
Endoglin
Membrane Proteins
medicine.disease
Penetrance
Pedigree
Phenotype
Telangiectasia, Hereditary Hemorrhagic
business
Haploinsufficiency
Subjects
Details
- ISSN :
- 13816128
- Volume :
- 12
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Current pharmaceutical design
- Accession number :
- edsair.doi.dedup.....82bd16cb0b5b1a8cab82c69ce807fa46