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

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


Rajiv D. Machado

Micheala A. Aldred

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 Parma

Marc 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


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?? 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.


Machado, R. D., Aldred, M. A., James, V., Harrison, R. E., Patel, B., Schwalbe, E. C., …Trembath, R. C. (2006). Mutations of the TGF-β type II receptor BMPR2 in pulmonary arterial hypertension. Human Mutation, 27(2), 121-132. doi:10.1002/humu.20285

Journal Article Type Article
Online Publication Date Jan 20, 2006
Publication Date 2006-02
Deposit Date Dec 6, 2018
Journal Human Mutation
Print ISSN 1059-7794
Electronic ISSN 1098-1004
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 27
Issue 2
Pages 121-132
Keywords Genetics(clinical); Genetics
Public URL
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