PT  - JOURNAL ARTICLE
AU  - R E Harrison
AU  - J A Flanagan
AU  - M Sankelo
AU  - S A Abdalla
AU  - J Rowell
AU  - R D Machado
AU  - C G Elliott
AU  - I M Robbins
AU  - H Olschewski
AU  - V McLaughlin
AU  - E Gruenig
AU  - F Kermeen
AU  - T Laitinen
AU  - N W Morrell
AU  - R C Trembath
TI  - Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia
AID  - 10.1136/jmg.40.12.865
DP  - 2003 Dec 01
TA  - Journal of Medical Genetics
PG  - 865--871
VI  - 40
IP  - 12
4099  - http://jmg.bmj.com/content/40/12/865.short
4100  - http://jmg.bmj.com/content/40/12/865.full
SO  - J Med Genet2003 Dec 01; 40
AB  - 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.