Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia
- R E Harrison1,
- J A Flanagan1,
- M Sankelo2,
- S A Abdalla3,
- J Rowell1,
- R D Machado1,
- C G Elliott4,
- I M Robbins5,
- H Olschewski6,
- V McLaughlin7,
- E Gruenig8,
- F Kermeen9,
- T Laitinen2,
- N W Morrell10,
- R C Trembath1
- 1Division of Medical Genetics, University of Leicester, Leicester, UK
- 2Department of Medical Genetics, University of Helsinki, Helsinki, Finland
- 3Cancer and Blood Research Programme, The Hospital for Sick Children, Toronto, Canada
- 4Pulmonary Department, LDS Hospital, Salt Lake City, Utah, USA
- 5Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, USA
- 6Department of Internal Medicine II, Justus Liebig University, Giessen, Germany
- 7Rush-Presbyterian-St Luke’s Medical Center, Chicago, Illinois, USA
- 8Department Internal Medicine III, University of Heidelberg, Germany
- 9Flinders Medical Centre, South Australia, Australia
- 10Department of Medicine, University of Cambridge, UK
- Correspondence to: Professor Richard C Trembath Division of Medical Genetics, Adrian Building, University of Leicester, University Road, Leicester LE1 7RH, UK;
- Received 1 July 2003
- Accepted 18 August 2003
Background: Mutations of the transforming growth factor β (TGFβ) 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.