BACKGROUND: Mutations of the transforming growth factor beta (TGFbeta) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. OBJECTIVE: To investigate kindreds presenting with both pulmonary hypertension and HHT. METHODS: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. RESULTS: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. CONCLUSIONS: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.
Pubmed ID: 14684682 RIS Download
Mesh terms: Activin Receptors, Type I | Activin Receptors, Type II | Adolescent | Adult | Aged | Amino Acid Sequence | Antigens, CD | Bone Morphogenetic Protein Receptors, Type II | DNA Mutational Analysis | Endoglin | Endoplasmic Reticulum | Female | Genetic Predisposition to Disease | Humans | Hypertension, Pulmonary | Male | Middle Aged | Models, Molecular | Mutation, Missense | Protein-Serine-Threonine Kinases | Receptors, Cell Surface | Structural Homology, Protein | Telangiectasia, Hereditary Hemorrhagic | Vascular Cell Adhesion Molecule-1
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