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dc.contributor.authorNasim, Md. Talat*
dc.contributor.authorGhouri, A.*
dc.contributor.authorPatel, B.*
dc.contributor.authorJames, V.*
dc.contributor.authorRudarakanchana, N.*
dc.contributor.authorMorrell, N.W.*
dc.contributor.authorTrembath, R.C.*
dc.date.accessioned2014-04-28T10:58:38Z
dc.date.available2014-04-28T10:58:38Z
dc.date.issued2008
dc.identifier.citationNasim, M. T., Ghouri, A., Patel, B., James, V., Rudarakanchana, N., Morrell, N. W., Trembath, R. C. (2008) Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Human Molecular Genetics, 17(11), 1683-1694.
dc.identifier.urihttp://hdl.handle.net/10454/6113
dc.descriptionNo
dc.description.abstractHeterozygous 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 (NMD) and receptor complex interactions. We demonstrate that nonsense and frameshift mutations trigger NMD, 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.
dc.language.isoen
dc.subjectAminoglycosides
dc.subjectPharmacology
dc.subjectBone morphogenetic protein receptors
dc.subjectType I
dc.subjectMetabolism
dc.subjectBone morphogenetic protein receptors
dc.subjectType II
dc.subjectGenetics
dc.subjectCodon
dc.subjectNonsense
dc.subjectExons
dc.subjectGenes
dc.subjectReporter
dc.subjectHumans
dc.subjectHypertension
dc.subjectPulmonary
dc.subjectEnzymology
dc.subjectIntrons
dc.subjectPhosphorylation
dc.subjectProtein biosynthesis
dc.subjectRNA precursors
dc.subjectRNA splicing
dc.subjectRNA stability
dc.subjectRNA
dc.subjectmessenger
dc.subjectSignal transduction
dc.subjectTranscription
dc.subjectDrug effects
dc.subjectREF 2014
dc.titleStoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension
dc.typeArticle
dc.type.versionNo full-text in the repository
dc.identifier.doihttps://doi.org/10.1093/hmg/ddn059
dc.openaccess.statusclosedAccess


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