Genetic aspects of pulmonary arterial hypertension

Abstract

This paper concentrates on the genetic aspects of pulmonary arterial hypertension (PAH), a diagnostically based subclass of pulmonary hypertension that includes primary pulmonary hypertension (PPH). During the past year, patients with familial and sporadic PPH were found to have germline heterozygous missense, nonsense and frameshift mutations in bone morphogenetic protein receptor II (BMPR2). Mutations in BMPR2, a member of the transforming growth factor-β (TGF-β) receptor superfamily, are predicted to interrupt the bone morphogenetic protein (BMP) signalling pathway, resulting in proliferation, rather than apoptosis of cells within small arterioles. Mechanistically, haploinsufficiency was found by using in vitro gene expression experiments, but a dominant-negative mechanism has not been excluded. The failure to find BMPR2 mutations in all families with familial PPH and in all patients with sporadic PPH suggests that other genes remain to be identified. Mutations in ALK1, a TGF-β type 1 receptor, previously known to cause type 2 hereditary haemorrhagic telangiectasia (HHT), have also been reported in a few HHT families with clinical and histological features of PPH. The clinical development of PPH, as in neoplasia, appears to require 'two hits'. The two hits can be provided either by genetic or environmental factors.