17 research outputs found
Hereditary haemorrhagic telangiectasia in North African and sub-Saharan patients
Hereditary haemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu disease is an autosomal-dominant inherited vascular disease, characterised by the presence of mucocutaneous telangiectasia and visceral arteriovenous malformations (AVMs). Three main causative genes are known: ENG, ACVRL1 and SMAD4. BMP9 has also been shown to be involved in a small number of cases. We report two cases of HHT in North African and sub-Saharan patients
Modelling of ALK1 ectodomain and ALK1-ActRIIA-BMP9 receptor complex: hints from Type 2 Hereditary Haemorrhagic Telangiectasia
Bioinformatic Analysis of Pathogenic Missense Mutationsof Activin Receptor Like Kinase 1 Ectodomain
Activin A receptor, type II-like kinase 1 (also called ALK1), is a serine-threonine kinase predominantly expressed on endothelial cells surface. Mutations in its ACVRL1 encoding gene (12q11-14) cause type 2 Hereditary Haemorrhagic Telangiectasia (HHT2), an autosomal dominant multisystem vascular dysplasia. The study of the structural effects of mutations is crucial to understand their pathogenic mechanism. However, while an X-ray structure of ALK1 intracellular domain has recently become available (PDB ID: 3MY0), structure determination of ALK1 ectodomain (ALK1(EC)) has been elusive so far. We here describe the building of a homology model for ALK1(EC), followed by an extensive bioinformatic analysis, based on a set of 38 methods, of the effect of missense mutations at the sequence and structural level. ALK1(EC) potential interaction mode with its ligand BMP9 was then predicted combining modelling and docking data. The calculated model of the ALK1(EC) allowed mapping and a preliminary characterization of HHT2 associated mutations. Major structural changes and loss of stability of the protein were predicted for several mutations, while others were found to interfere mainly with binding to BMP9 or other interactors, like Endoglin (CD105), whose encoding ENG gene (9q34) mutations are known to cause type 1 HHT. This study gives a preliminary insight into the potential structure of ALK1(EC) and into the structural effects of HHT2 associated mutations, which can be useful to predict the potential effect of each single mutation, to devise new biological experiments and to interpret the biological significance of new mutations, private mutations, or non-synonymous polymorphisms
Hereditary haemorrhagic telangiectasia in North African and sub-Saharan patients
Hereditary haemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu disease is an autosomal-dominant inherited vascular disease, characterised by the presence of mucocutaneous telangiectasia and visceral arteriovenous malformations (AVMs). Three main causative genes are known: ENG, ACVRL1 and SMAD4. BMP9 has also been shown to be involved in a small number of cases. We report two cases of HHT in North African and sub-Saharan patients
Bioinformatic analysis of pathogenic missense mutations of activin receptor like kinase 1 ectodomain.
Activin A receptor, type II-like kinase 1 (also called ALK1), is a serine-threonine kinase predominantly expressed on endothelial cells surface. Mutations in its ACVRL1 encoding gene (12q11-14) cause type 2 Hereditary Haemorrhagic Telangiectasia (HHT2), an autosomal dominant multisystem vascular dysplasia. The study of the structural effects of mutations is crucial to understand their pathogenic mechanism. However, while an X-ray structure of ALK1 intracellular domain has recently become available (PDB ID: 3MY0), structure determination of ALK1 ectodomain (ALK1(EC)) has been elusive so far. We here describe the building of a homology model for ALK1(EC), followed by an extensive bioinformatic analysis, based on a set of 38 methods, of the effect of missense mutations at the sequence and structural level. ALK1(EC) potential interaction mode with its ligand BMP9 was then predicted combining modelling and docking data. The calculated model of the ALK1(EC) allowed mapping and a preliminary characterization of HHT2 associated mutations. Major structural changes and loss of stability of the protein were predicted for several mutations, while others were found to interfere mainly with binding to BMP9 or other interactors, like Endoglin (CD105), whose encoding ENG gene (9q34) mutations are known to cause type 1 HHT. This study gives a preliminary insight into the potential structure of ALK1(EC) and into the structural effects of HHT2 associated mutations, which can be useful to predict the potential effect of each single mutation, to devise new biological experiments and to interpret the biological significance of new mutations, private mutations, or non-synonymous polymorphisms
Bioinformatic Analysis of Pathogenic Missense Mutations of Activin Receptor Like Kinase 1 Ectodomain
Canzonieri Cecilia; Ornati Federica; Matti Elina; Chu Francesco; Manfredi Guido; Olivieri Carla; Buscarini Elisabetta; Pagella Fabio; Cesare Danesino.
Immunohistochemical analysis of a merkeloma observed in a patient affected byhereditary haemorrhagic telangiectasia.
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterised by
epistaxis, telangiectases, and multiorgan vascular dysplasia. Mutations of the ENG and ACVRL1 genes
cause at least 80% of cases. We report the first case of merkeloma found in a patient with HHT carrying
an ENG mutation. We analysed the tumour with immunohistochemical methods using primary
antibodies against CD105 (endoglin), TGF-Ξ², Smad4, CD31 and CD34. Tumour cells were positive for
Smad4, weakly positive for TGF-Ξ², and negative for CD105. Vasal endothelial cells were highly positive
for CD105, CD31 and CD34. No remarkable differences between cancer and normal cells in our patient
or between the patientβs merkeloma and two control merkelomas were observed. The presence of a
merkeloma in an HHT patient could be an occasional association, but to certainly assume it further
investigations are needed