Mutations of the TGF-β type II receptor BMPR2 in pulmonary arterial hypertension

Rajiv D. Machado, Micheala A. Aldred, Victoria James, Rachel E. Harrison, Bhakti Patel, Edward C. Schwalbe, Ekkehard Gruenig, Bart Janssen, Rolf Koehler, Werner Seeger, Oliver Eickelberg, Horst Olschewski, C. Gregory Elliott, Eric Glissmeyer, John Carlquist, Miryoung Kim, Adam Torbicki, Anna Fijalkowska, Grzegorz Szewczyk, Jasmine ParmaMarc J. Abramowicz, Nazzareno Galie, Hiroko Morisaki, Shingo Kyotani, Norifumi Nakanishi, Takayuki Morisaki, Marc Humbert, Gerald Simonneau, Olivier Sitbon, Florent Soubrier, Florence Coulet, Nicholas W. Morrell, Richard C. Trembath*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

338 Citations (Scopus)


Pulmonary arterial hypertension (PAH) is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality. The disorder is typically sporadic, and in such cases the term idiopathic PAH (IPAH) is used. However, cases that occur within families (familial PAH (FPAH)) display similar clinical and histopathological features, suggesting a common etiology. Heterozygous mutations of a type II member of the TGF-β cell signaling superfamily known as BMPR2 on chromosome 2q33 have been identified in many kindreds with FPAH, yet display both reduced penetrance and sex bias. This report presents the compilation of data for 144 distinct mutations that alter the coding sequence of the BMPR2 gene identified in 210 independent PAH subjects. This large data set characterizes the extent of sequence variation and reveals that the majority (71%) of mutations in FPAH and IPAH comprise nonsense, frameshift, and splice-site defects, and gene rearrangements. These predict premature termination of the transcript with likely loss through the process of nonsense-mediated decay (NMD). A total of 44 missense mutations were identified that substitute amino acid residues at highly conserved sites within recognized functional domains of the mature receptor. We assess this category of mutations in the context of their heterogeneous effects on cell signaling when assayed by in vitro cell-based systems. Disease-causing mutation hot-spots within BMPR2 are summarized. Taken together, these observations are likely to aid in the development of targeted mutation detection strategies relevant for patient management. Finally, we examine the age- and sex-dependent reduced penetrance of BMPR2 mutations by reviewing bmpr2 animal models and the requirement for additional genetic and/or environmental modifiers of disease. In conclusion, these data provide compelling genetic evidence that haploinsufficiency is the predominant molecular mechanism underlying disease predisposition, and support the concept of a critical threshold of signaling activity below which disease may be precipitated.

Original languageEnglish
Pages (from-to)121-132
Number of pages12
JournalHuman Mutation
Issue number2
Publication statusPublished - Feb 2006
Externally publishedYes

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