{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T03:12:09Z","timestamp":1793416329062,"version":"4.5.0"},"reference-count":30,"publisher":"BMJ","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[2003,12]]},"abstract":"<jats:p>\n                  <jats:bold>Background:<\/jats:bold> Mutations of the transforming growth factor \u03b2 (TGF\u03b2) receptor components <jats:italic>ENDOGLIN<\/jats:italic> and <jats:italic>ALK-1<\/jats:italic> cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor <jats:italic>BMPR2<\/jats:italic> underlie familial primary pulmonary hypertension.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Objective:<\/jats:bold> To investigate kindreds presenting with both pulmonary hypertension and HHT.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Methods:<\/jats:bold> Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of <jats:italic>ALK-1<\/jats:italic>, <jats:italic>ENDOGLIN<\/jats:italic>, and <jats:italic>BMPR2<\/jats:italic> 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.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Results:<\/jats:bold> Molecular analysis of 11 probands identified eight missense mutations of <jats:italic>ALK-1<\/jats:italic>, one of which was observed in two families. Mutations were located within exons 5 to 10 of the <jats:italic>ALK-1<\/jats:italic> gene. The majority of <jats:italic>ALK-1 <\/jats:italic>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 <jats:italic>ENDOGLIN<\/jats:italic>.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Conclusions:<\/jats:bold> 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 <jats:italic>ALK-1<\/jats:italic> and <jats:italic>BMPR2<\/jats:italic> that cause inherited pulmonary vascular disease.<\/jats:p>","DOI":"10.1136\/jmg.40.12.865","type":"journal-article","created":{"date-parts":[[2003,12,18]],"date-time":"2003-12-18T18:38:05Z","timestamp":1071772685000},"page":"865-871","source":"Crossref","is-referenced-by-count":320,"title":["Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia"],"prefix":"10.1136","volume":"40","author":[{"given":"R E","family":"Harrison","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J 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