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GENETIC CAUSES OF PULMONARY ARTERIAL HYPERTENSION
Abstract
Pulmonary arterial hypertension is a rare disorder that may be hereditable pulmonary arterial
hypertension, idiopathic pulmonary arterial hypertension, or associated with either drug toxin
exposures or other medical condition. Majority of cases of inherited (familial) pulmonary
arterial hypertension show mutations in two receptors, bone morphogenetic protein receptor
type 2 (BMPR2) and activin like kinase-type 1 (ALK-1), of the transforming growth factor-β
(TGF-β) family. Mutations (especially exonic mutations) in BMPR2 are found in majority of
patients with familial pulmonary arterial hypertension, and ALK-1 mutations are found in a
minority of patients with hereditary haemorrhagic telangiectasia and co-existent pulmonary
arterial hypertension. Familial pulmonary arterial hypertension is highly linked to
chromosome 2q33 and remaining family cases without exonic mutations have either intronic
BMPR2 abnormalities or alteration in the promoter or regulatory genes. Imbalanced
activation of other TGF-β receptors coupled with reduced activity of mutated BMPR2
increases the likelihood of development of pulmonary arterial hypertension. Approaches to
altering the imbalance of activation of BMPR2 and other TGF-β receptor may yield future
therapies for pulmonary arterial hypertension. Advances in genetic testing, pre-symptomatic
screening, and biomarkers should permit early detection of disease in those at risk of
pulmonary arterial hypertension and thereby design preventive therapy in its carriers.
Keywords: PAH, TGF-β, BMPR2, ALK-1