ORIGINAL ARTICLE

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

¹ Division of Medical Genetics, University of Leicester, Leicester, UK
² Department of Medical Genetics, University of Helsinki, Helsinki, Finland
³ Cancer and Blood Research Programme, The Hospital for Sick Children, Toronto, Canada
⁴ Pulmonary Department, LDS Hospital, Salt Lake City, Utah, USA
⁵ Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, USA
⁶ Department of Internal Medicine II, Justus Liebig University, Giessen, Germany
⁷ Rush-Presbyterian-St Luke’s Medical Center, Chicago, Illinois, USA
⁸ Department Internal Medicine III, University of Heidelberg, Germany
⁹ Flinders Medical Centre, South Australia, Australia
¹⁰ Department of Medicine, University of Cambridge, UK

Correspondence to:
Correspondence to:
Professor Richard C Trembath
Division of Medical Genetics, Adrian Building, University of Leicester, University Road, Leicester LE1 7RH, UK; rtrembat{at}hgmp.mrc.ac.uk

Background: Mutations of the transforming growth factor ß (TGFß) 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.

Keywords: pulmonary hypertension; hereditary haemorrhagic telangiectasia; ALK-1; BMPR-II; TGFß

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