Pulmonary arterial hypertension (PAH) can be idiopathic, hereditary, or develop in association with other diseases. Hereditary PAH is inherited as an autosomal dominant trait with reduced penetrance and variable age of onset. Heterozygous mutations in BMPR2, encoding a type II receptor in the TGF-β signalling pathway, underlie the majority of hereditary cases of PAH. PAH can occur as a rare complication of hereditary haemorrhagic telangiectasia (HHT), a vascular dysplasia caused by mutations in ALK-1, encoding a type I TGF-β receptor and ENG, encoding the accessory TGF-β receptor endoglin. BMP signalling plays an important role in cardiac embryogenesis and PAH is a common complication of congenital heart disease.\ud In this thesis clinical and molecular studies have been performed upon a number of subjects, including those presenting with the combination of HHT and pulmonary hypertension, children presenting with PAH in childhood, and a cohort of adults and children presenting with congenital heart defects unselected for the presence of PAH. Novel heterozygous mutations were identified within the gene encoding ALK-1 and cell-based functional analysis was undertaken to characterise the consequences of these molecular defects. Novel single base pair substitutions in BMPR2 were identified in association with cardiac defects of the outflow tract, indicating that disrupted BMPRII signalling may play a role in the pathogenesis of congenital heart disease.\ud Segregation analysis to determine allele-specific penetrance in a single multigenerational kindred demonstrated that penetrance was significantly higher than previous estimates with profound implications for clinical screening and management of families with hereditary PAH.\ud Taken together, these studies provide insight into the molecular genetic basis of PAH, and identify disrupted signalling in the TGF-β cell-signalling pathway as a fundamental primary defect in the pathophysiology of this devastating disorder
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