Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia

R E Harrison, J A Flanagan, M Sankelo, S A Abdalla, J Rowell, R D Machado, C G Elliott, I M Robbins, H Olschewski, V McLaughlin, E Gruenig, F Kermeen, T Laitinen, N W Morrell, R C Trembath

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289 Citations (Scopus)

Abstract

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
Original languageEnglish
Pages (from-to)865 - 871
Number of pages7
JournalJournal of Medical Genetics
Volume40
Issue number12
DOIs
Publication statusPublished - Dec 2003

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