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 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.

Keywords: ACVRL1; BMPR2; CAV1; EIF2AK4; ENG; KCNA5; KCNK3; SMAD1; SMAD4; SMAD9; haploinsufficiency; locus heterogeneity.

Figure 1

Schematic of canonical BMP signaling and additional pathways implicated in PAH pathogenesis by conventional and next-generation sequence analysis. Causal genes are indicated by the asterisks.

Figure 2

A) Distribution of reported exonic mutations across the BMPR2 gene. Black bars represent all mutation categories; grey bars indicate missense mutations only. This graph excludes data from non-coding regions and gene rearrangements for which start and/or end points have not been conclusively determined. B) Proportion of distinct point mutations relative to exon size. Multiple and/or recurrent variants at the same nucleotide were counted as a single event. The total number of mutated residues confined to the open-reading frame was calculated as a percentage of exon length in nucleotides.

Figure 3

Three-dimensional structure of the BMPR-II extracellular domain highlighting the location of substitutions impacting upon 9 of the 10 key cysteine residues responsible for disulfide bridge formation, indicated in dark blue. Defects in the Cys116 residue have not been identified in PAH thus far. Figure was reproduced from the crystal structure (PDB ID: 2HLQ) and processed using Cn3D v4.3 software.