Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Dec;36(12):1113-27.
doi: 10.1002/humu.22904. Epub 2015 Oct 12.

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

Rajiv D Machado  1 , Laura Southgate  2   3 , Christina A Eichstaedt  4   5 , Micheala A Aldred  6 , Eric D Austin  7 , D Hunter Best  8   9 , Wendy K Chung  10 , Nicola Benjamin  4 , C Gregory Elliott  11 , Mélanie Eyries  12   13   14 , Christine Fischer  5 , Stefan Gräf  15   16 , Katrin Hinderhofer  5 , Marc Humbert  17   18   19 , Steven B Keiles  20 , James E Loyd  21 , Nicholas W Morrell  15   22 , John H Newman  21 , Florent Soubrier  12   13   14 , Richard C Trembath  2 , Rebecca Rodríguez Viales  4   5 , Ekkehard Grünig  4
Affiliations
Review

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

Rajiv D Machado et al. Hum Mutat. 2015 Dec.

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.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest: The authors declare no conflicts of interest.

Figures

Figure 1
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
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
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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abdalla SA, Gallione CJ, Barst RJ, Horn EM, Knowles JA, Marchuk DA, Letarte M, Morse JH. Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia. Eur Respir J. 2004;23:373–377. - PubMed
    1. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet Chapter 7. 2013;Unit7:20. - PMC - PubMed
    1. Aldred MA, Vijayakrishnan J, James V, Soubrier F, Gomez-Sanchez MA, Martensson G, Galie N, Manes A, Corris P, Simonneau G, Humbert M, Morrell NW, et al. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat. 2006;27:212–213. - PubMed
    1. Aldred MA, Machado RD, James V, Morrell NW, Trembath RC. Characterization of the BMPR2 5′-untranslated region and a novel mutation in pulmonary hypertension. Am J Respir Crit Care Med. 2007;176:819–824. - PubMed
    1. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation. 2010;121:2045–2066. - PMC - PubMed

Publication types

MeSH terms

Substances