ArticlePloS one2013
Abnormal trafficking of endogenously expressed BMPR2 mutant allelic products in patients with heritable pulmonary arterial hypertension.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- The double whammy of ER-retention and dominant-negative effects in numerous autosomal dominant diseases: significance in disease mechanisms and therapy.Journal of biomedical science · 2024Review
- Review
- Review
- Genes in pediatric pulmonary arterial hypertension and the most promisingFrontiers in genetics · 2022Review
- Approaches to treat pulmonary arterial hypertension by targeting BMPR2: from cell membrane to nucleus.Cardiovascular research · 2021Review
- An endothelial activin A-bone morphogenetic protein receptor type 2 link is overdriven in pulmonary hypertension.Nature communications · 2021Article
- Endoplasmic Reticulum Associated Protein Degradation (ERAD) in the Pathology of Diseases Related to TGFβ Signaling Pathway: Future Therapeutic Perspectives.Frontiers in molecular biosciences · 2020Review
- BMPR2 acts as a gatekeeper to protect endothelial cells from increased TGFβ responses and altered cell mechanics.PLoS biology · 2019Article
- Article
- New and Emerging Therapies for Pulmonary Arterial Hypertension.Annual review of medicine · 2019Review
- BMP type II receptor as a therapeutic target in pulmonary arterial hypertension.Cellular and molecular life sciences : CMLS · 2017Review
- Differential molecular regulation of processing and membrane expression of Type-I BMP receptors: implications for signaling.Cellular and molecular life sciences : CMLS · 2017Article
- Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension.Scientific reports · 2017Article
- The role of genetics in pulmonary arterial hypertension.The Journal of pathology · 2017Review
- Genotype-phenotype effects ofPulmonary circulation · 2016Article
- Differential regulation of translation and endocytosis of alternatively spliced forms of the type II bone morphogenetic protein (BMP) receptor.Molecular biology of the cell · 2016Article
- 4-Phenylbutyric Acid Induces Protection against Pulmonary Arterial Hypertension in Rats.PloS one · 2016Article
- ER reorganization is remarkably induced in COS-7 cells accumulating transmembrane protein receptors not competent for export from the endoplasmic reticulum.The Journal of membrane biology · 2014Article
- N-linked glycosylation of the bone morphogenetic protein receptor type 2 (BMPR2) enhances ligand binding.Cellular and molecular life sciences : CMLS · 2014Article
- Cytokines trigger disruption of endothelium barrier function and p38 MAP kinase activation inPulmonary circulationArticle
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
More than 200 heterozygous mutations in the type 2 BMP receptor gene, BMPR2, have been identified in patients with Heritable Pulmonary Arterial Hypertension (HPAH). More severe clinical outcomes occur in patients with BMPR2 mutations by-passing nonsense-mediated mRNA decay (NMD negative mutations). These comprise 40% of HPAH mutations and are predicted to express BMPR2 mutant products. However expression of endogenous NMD negative BMPR2 mutant products and their effect on protein trafficking and signaling function have never been described. Here, we characterize the expression and trafficking of an HPAH-associated NMD negative BMPR2 mutation that results in an in-frame deletion of BMPR2 EXON2 (BMPR2ΔEx2) in HPAH patient-derived lymphocytes and in pulmonary endothelial cells (PECs) from mice carrying the same in-frame deletion of Exon 2 (Bmpr2 (ΔEx2/+) mice). The endogenous BMPR2ΔEx2 mutant product does not reach the cell surface and is retained in the endoplasmic reticulum. Moreover, chemical chaperones 4-PBA and TUDCA partially restore cell surface expression of Bmpr2ΔEx2 in PECs, suggesting that the mutant product is mis-folded. We also show that PECs from Bmpr2 (ΔEx2/+) mice have defects in the BMP-induced Smad1/5/8 and Id1 signaling axis, and that addition of chemical chaperones restores expression of the Smad1/5/8 target Id1. These data indicate that the endogenous NMD negative BMPRΔEx2 mutant product is expressed but has a folding defect resulting in ER retention. Partial correction of this folding defect and restoration of defective BMP signaling using chemical chaperones suggests that protein-folding agents could be used therapeutically in patients with these NMD negative BMPR2 mutations.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.