ALK-1 (activin receptor-like kinase-1), a type I receptor of the transforming growth factor (TGF)-beta superfamily, is the gene mutated in hereditary hemorrhagic telangiectasia type 2 (HHT2) while endoglin is mutated in HHT1. Using a novel polyclonal antibody to ALK-1, we measured ALK-1 expression on human umbilical vein endothelial cells (HUVEC) of newborns from HHT families whose affected members had normal endoglin levels. ALK-1 levels were specifically reduced in three HUVEC with ALK-1 missense mutant codons, and normal in two newborns not carrying the missense mutations present in the clinically affected relatives. Levels were also normal in a HUVEC with deletion of S232 in the ATP binding site of ALK-1. Thus HHT2 appears to be associated with a loss of function of the mutant allele due to a reduction in either protein level or activity. We also report three new ALK-1 missense mutations leading to G48E/A49P, C344Y and E407D substitutions. In COS-1 transfected cells, ALK-1 was found in the TGF-beta1 and -beta3 receptor complexes in association with endoglin and TbetaRII, but not in activin receptor complexes containing endoglin. In HUVEC, ALK-1 was not detectable in the TGF-beta1 or -beta3 receptor complexes. However, in the absence of ligand, ALK-1 and endoglin interactions were observed by immunoprecipitation/western blot in HUVEC from normal as well as HHT1 and HHT2 patients. Our data suggest a transient association between these two proteins of the TGF-beta superfamily, both required at a critical level to ensure vessel wall integrity.
For most missense variants of ENG and ACVRL1 reported to date, study of amino acid conservation showed good concordance between prediction of altered protein function and disease occurrence. The 39 families (20%) yet to be resolved may carry ENG, ACVRL1, or MADH4 mutations too complex or difficult to detect, or mutations in genes yet to be identified.
Primary pulmonary hypertension (PPH) is a rare but severe and progressive disease characterised by obstructive lesions of small pulmonary arteries. Patients with PPH often have mutations in the bone morphogenetic protein receptor type II (BMPR2) gene, whereas some carry mutations in the activin receptor-like kinase 1 (ALK-1) gene, generally associated with hereditary haemorrhagic telangiectasia (HHT) type 2, a vascular dysplasia affecting multiple organs. The aim of this study was to determine whether members of families with PPH and confirmed or probable HHT had ALK-1 mutations.ALK-1 and BMPR2 mutation analysis was performed on deoxyribonucleic acid from affected members of four families with PPH and confirmed or suspected HHT.ALK-1 mutations were identified in all four families and three novel mutations found in exon 10, leading to truncated proteins. In the fourth family, a missense mutation, previously reported in four independent HHT families, was detected in exon 8. Analysis of the BMPR2 gene revealed no exonic mutations in the probands with both PPH and HHT.The present data bring to 10 the number of reported families with primary pulmonary hypertension and hereditary haemorrhagic telangiectasia type 2, representing 16% of the 61 families with known activin receptor-like kinase 1 mutations. Such mutations might predispose to primary pulmonary hypertension, and specialists should be aware of the potential link between these two disorders. Primary pulmonary hypertension (PPH) is a rare disease with an estimated incidence of 1-2 cases per million population [1]. The presenting symptoms usually include fatigue, anorexia and shortness of breath, which, if left untreated, lead to a progressive increase in pulmonary arterial pressure, right ventricular failure and death [2]. The affected small pulmonary arteries and arterioles are characterised by intimal proliferation, medial hypertrophy, concentric fibrosis and the presence of plexiform lesions composed of both vascular smooth muscle cells and endothelial cells [3]. Monoclonal endothelial cell proliferation is found in the plexiform lesions of PPH but not in secondary pulmonary hypertension [4].Recently, PPH has been found to be caused by mutations in either of two genes: the bone morphogenetic protein receptor type II gene (BMPR2) [5][6][7] and the activin receptor-like kinase 1 gene (ACVRL1 or ALK-1) [8], both members of the transforming growth factor-b (TGF-b) receptor superfamily. A recent abstract reported an endoglin gene (ENG) mutation in a patient with HHT and dexfenfluramine-associated PPH [9]. ALK-1 and ENG are the two genes associated with hereditary haemorrhagic telangiectasia (HHT). Mutations in ALK-1 lead to HHT type 2 (HHT2) [10,11], whereas mutations in ENG are responsible for HHT type 1 (HHT1) [12]. HHT is an autosomal dominant vascular disorder that occurs at an incidence of w1 in 10,000 population. It is characterised by vascular dysplasia with the formation of mucocutaneous telangiectases and arteriovenous malformations (AVMs) in ...
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