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


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.

  • pulmonary hypertension
  • hereditary haemorrhagic telangiectasia
  • ALK-1
  • TGFβ

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