Human Molecular Genetics Advance Access published online on March 4, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn059
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Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension
1 King's College London, Dept. of Medical and Molecular Genetics, Guy's Hospital, London SE1 9RT, UK 2 Dept. of Genetics, University of Leicester, Leicester LE1 7RH, UK 3 Dept. of Medicine, University of Cambridge, Cambridge, UK
* Corresponding author: Dr. T. Nasim King's College London Dept. of Medical and Molecular Genetics Guy's Hospital London SE1 9RT, UK Tel. 0207 188 9505 Fax 0207 188 2585 E-mail talat.nasim{at}genetics.kcl.ac.uk
Correspondence may also be addressed to: Professor R. C Trembath, King's College London, Dept. of Medical and Molecular Genetics Guy's Hospital London SE1 9RT, UK Tel: +44 (0) 20-7188-7994 Fax: +44 (0) 20-7188-8050 E-mail Richard.trembath{at}genetics.kcl.ac.uk
Received December 21, 2007; Revised February 22, 2008; Accepted February 22, 2008
Heterozygous germline defects in a gene encoding a type II receptor for bone morphogenetic proteins (BMPR-II), underlie the majority of inherited cases of the vascular disorder known as pulmonary arterial hypertension (PAH). However, the precise molecular consequences of PAH causing mutations on the function of the receptor complex remain unclear. We employed novel enzymatic and fluorescence activity based techniques to assess the impact of PAH mutations on pre-mRNA splicing, nonsense-mediated decay and receptor complex interactions. We demonstrate that nonsense and frameshift mutations trigger nonsense-mediated decay, providing further evidence that haplo-insufficiency is a major molecular consequence of disease related BMPR2 mutations. We identified heterogeneous functional defects in BMPR-II activity, including impaired type I receptor phosphorylation, receptor interactions and altered receptor complex stoichiometry leading to perturbation of downstream signalling pathways. Importantly, these studies demonstrate that the intracellular domain of BMPR-II is both necessary and sufficient for receptor complex interaction. Finally and to address the potential for resolution of stoichiometric balance, we investigated an agent that promotes translational readthrough of a BMPR2 nonsense reporter construct without interfering with the NMD pathway. We propose that stoichiometric imbalance, due to either haplo-insufficiency or loss of optimal receptor-receptor interactions impairs BMPR-II mediated signalling in PAH. Taken together, these studies have identified an important target for early therapeutic intervention in familial PAH.
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