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

Rajiv D Machado, Laura Southgate, Christina A Eichstaedt, Micheala A Aldred, Eric D Austin, D Hunter Best, Wendy K Chung, Nicola Benjamin, C Gregory Elliott, Mélanie Eyries, Christine Fischer, Stefan Gräf, Katrin Hinderhofer, Marc Humbert, Steven B Keiles, James E Loyd, Nicholas W Morrell, John H Newman, Florent Soubrier, Richard C TrembathRebecca Rodríguez Viales, Ekkehard Grünig

Research output: Contribution to journalArticlepeer-review

178 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1113-27
Number of pages15
JournalHuman Mutation
Issue number12
Publication statusPublished - Dec 2015


  • Animals
  • Bone Morphogenetic Protein Receptors, Type II
  • Disease Models, Animal
  • Genetic Association Studies
  • Genetic Counseling
  • Genetic Predisposition to Disease
  • Genetic Variation
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hypertension, Pulmonary
  • Multigene Family
  • Mutation
  • Signal Transduction
  • Transforming Growth Factor beta


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