Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects

Abstract

Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta (TGF-β) pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG) and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, maintenance and pathogenetic transformation of the pulmonary vascular bed. Together, these analyses represent the largest comprehensive compilation of BMPR2 and associated genetic risk factors for PAH, comprising known and novel variation. Additionally, with the inclusion of an allelic series of locus-specific variation in BMPR2, these data provide a key resource in data interpretation and development of contemporary therapeutic and diagnostic tools.

Genetic counselling in a national referral centre for pulmonary hypertension

“…This gene encodes a type II receptor (BMPRII) belonging to the superfamily of transforming growth factor (TGF)-β [7][8][9][10]. The BMPRII receptor was originally described to be involved in the regulation of growth and differentiation of bone and cartilage [11,12], but more recently, it was also shown to play a critical role in the regulation of growth, differentiation and apoptosis of other cell types, including endothelial cells and pulmonary artery smooth muscle cells [13].When PAH occurs in a familial context, germline mutations in BMPR2 are detected in at least 70% of cases [14][15][16][17][18][19]. BMPR2 mutations can also be detected in 3.5-40% of apparently sporadic PAH cases [14][15][16]20].…”

“…Recently, we have demonstrated the involvement of bi-allelic mutations in the EIF2AK4 (eukaryotic translation initiation factor 2α kinase 4) gene in the development of heritable PVOD [19,29]. PVOD due to EIF2AK4 mutations is an autosomal recessive disease with an unknown penetrance.…”

The Evolving Classification of Pulmonary Hypertension

“…Next-generation sequencing analysis has allowed for identification of genes associated with PAH outside the TGF-b superfamily, including CAV1 and KCNK3. 27 The roles and mechanisms of these proteins are still under investiga- tion. Mutations in BMPR2 are inherited in an autosomaldominant fashion, but incomplete penetrance and gender bias favoring females suggest environmental and/or other endogenous factors have important disease-modifying roles.…”

Is Elevated Circulating Galectin-3 Level A Predictor of Pulmonary Artery Hypertension Development and Progression?

“…There is evidence regarding the role of pulmonary arterial smooth muscle and endothelial cells in vasoconstriction, development of vasoocclusive lesions and ventilation-perfusion mismatch [34]. Therefore, PAH might occur due to several molecular mechanisms resulting in heterogeneous genetic defects affecting defects of the transforming growth factor beta pathway that could be regulated with Gal-3 [35]. At this pathway, Gal-3 may play a pivotal role in establishment and progression of PAH via inducing of endothelial dysfunction and hyperplasia of the underlying medial layer potentially through direct activation of (TGF)-beta/Smad3 signaling.…”