Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study investigated whether patients developing pulmonary arterial hypertension (PAH) after exposure to the appetite suppressants fenfluramine and dexfenfluramine have mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, as reported in primary pulmonary hypertension. BMPR2 was examined for mutations in 33 unrelated patients with sporadic PAH, and in two sisters with PAH, all of whom had taken fenfluramine derivatives, as well as in 130 normal controls. The PAH patients also underwent cardiac catheterisation and body mass determinations. Three BMPR2 mutations predicting changes in the primary structure of the BMPR-II protein were found in three of the 33 unrelated patients (9%), and a fourth mutation was found in the two sisters. No BMPR2 mutations were identified in the 130 normal controls. This difference in frequency was statistically significant. Moreover, the mutation-positive patients had a somewhat shorter duration of fenfluramine exposure before illness than the mutation-negative patients, a difference that was statistically significant when the two sisters were included in the analysis. In conclusion, the present authors have detected bone morphogenetic protein receptor 2 mutations that appear to be rare in the general population but may combine with exposure to fenfluramine derivatives to greatly increase the risk of developing severe pulmonary arterial hypertension.
...
PMID:BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. 1235 23

We report a large monocentric case series of 82 patients with human immunodeficiency virus-associated pulmonary arterial hypertension (PAH). No germline mutations of the PPH1 gene (bone morphogenetic protein receptor-II) were found in any of the 19 patients tested. PAH was the direct cause of death in 72% of cases. Survival rates of the overall population at 1, 2, and 3 years were 73, 60, and 47%, respectively. Survival was significantly poorer in patients in New York Heart Association functional class III-IV at the time of diagnosis, as compared with those in functional class I-II with respective rates of 60, 45, and 28% versus 100, 90, 84% at 1, 2, and 3 years (p < 0.0001). Subsequently, we analyzed prognostic factors in patients in functional class III-IV. Univariate analysis indicated that CD4 lymphocyte count of more than 212 cells mm(-3), the use of combination antiretroviral therapy (CART), and epoprostenol infusion were related with a better survival. On multivariate analysis only CD4 lymphocyte count was an independent predictor of survival, presumably because CART and epoprostenol infusion were strongly linked in our patient population. These results suggest that patients with severe human immunodeficiency virus-associated PAH should be considered for long-term epoprostenol infusion in association with CART.
...
PMID:Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension. 1261 32

Methods for determining protein-protein interactions in mammalian cells typically rely on single reporter functions and are susceptible to variations between samples particularly in regard to levels of transcription, processing and translation. A method has been developed for determining protein-protein interactions in mammalian cells, which bypasses these variables confounding single reporter assays. The approach utilizes two units of gene expression linked to reporter functions that are interposed by a deactivation-activation unit in such a way that the downstream expression unit is switched off. Hence upstream expression occurs regardless of protein-protein interaction, leading to the production of the upstream reporter. In the event of protein-protein interactions, the downstream expression unit is switched on leading to dual reporter read outs. Thus, the ratio of the two reporter activities provides a measure to determine the efficiency of protein-protein interactions. To access the system we screened a mutant of BMPR2 where the interaction between BMPR-II and LIMK is abrogated. BMPR-II is a type II receptor of the TGFbeta superfamily and plays a key role in the pathogenesis of familial pulmonary arterial hypertension. This system has potential for high-throughput screening of libraries (peptide, chemical, cDNA, etc.) to isolate agents that are capable of interfering with highly selective protein-protein interaction.
...
PMID:A dual-light reporter system to determine the efficiency of protein-protein interactions in mammalian cells. 1582 58

A variety of mutations in the bone morphogenetic protein receptor type 2 (BMPR2) have been identified in patients with pulmonary arterial hypertension. In this study, using our BMPR2 mutation database and BMPR-II protein sequences from eight distantly related species, we defined the relationship among evolutionary conservation, mutation frequency and mutation distribution. As a whole, BMPR2 is evolving slower than the average for mammalian protein-encoding genes. As expected, the kinase domain is evolving more slowly than the extracellular ligand-binding and C-terminal domains. A detailed map of evolutionary conservation shows that there are repeating peaks and valleys within the C-terminal domain, representing higher and lower evolutionary conservation. We observed a strong correlation between evolutionary conservation and the distribution of mutations along the gene. All except two, of the nineteen missense mutations occur in absolutely conserved amino acids among the vertebrate homologs. In addition, we identified six mutational hotspots (P<0.05) by comparing the observed distribution of mutations to the pattern expected from a random multinomial distribution. Furthermore, analysis of the sequence environment surrounding the mutations revealed a specific pattern of mutagenesis. Over 22% of all single base-paired substitutions and 30% of all deletions and insertions are situated within tandem or non-tandem direct repeats of at least 5-bp and may be explained by slipped-mispairing model of mutagenesis. Also, over 59% of single base-paired substitutions versus 20% of deletions and insertions are located in perfect palindromic sequences that could produce "hairpin-loop" secondary structures with relatively high thermodynamic stability under physiological conditions. In addition, 3.7% of single base-paired substitutions versus 30% of deletions and insertions are located either within or in close proximity to the Krawczak and Cooper consensus sequence (TG A/G A/G G/T A/C). Further study of the mechanism of mutagenesis in BMPR2 may help identify other potentially mutable sites and differentiate between deleterious mutations and harmless polymorphic variants.
...
PMID:Evolutionary conservation and mutational spectrum of BMPR2 gene. 1636 Oct 68

Mutations in the bone morphogenetic protein (BMP) type II receptor (BMPR2) gene cause familial pulmonary arterial hypertension (FPAH), a disease characterized by excessive smooth muscle and endothelial cell proliferation. However, the specific receptors mediating responses to BMPs in human vascular cells are not known. We show that human pulmonary artery smooth muscle cells (HPASMCs) express high specific (125)I-BMP4 binding, whereas human microvascular endothelial cells (HMEC-1) and human pulmonary artery endothelial cells (HPAECs) exhibit low binding. BMP4 competes for both high- and low-affinity (125)I-BMP4 binding sites on HPASMCs, yet BMP2 competes only at the low-affinity binding sites. In addition, BMP4, but not BMP2, induced Smad1/5 phosphorylation at low concentrations in HPASMCs. Conversely, HMEC-1 cells exhibited a single binding site population with equal affinity for BMP2 and BMP4. In both cell types, growth differentiation factor-5 (GDF5), BMP6, and BMP7 stimulated Smad1/5 phosphorylation and competed for (125)I-BMP4 less efficiently than BMP2 or BMP4. HPAECs exhibited weak Smad responses to BMPs. Expression analysis suggested the low binding in endothelial cells corresponded to lower ALK3 and ALK6 expression. Although transfection of small interfering RNAs (siRNAs) for ALK3 and BMPR-II abrogated Smad1/5 phosphorylation to BMP4, BMP2, and GDF5 in HMEC-1 and HPASMCs, they had little effect on (125)I-BMP4 binding. ALK6 siRNA did not alter binding or Smad1/5 responses, even to GDF5, a reported ALK6 selective ligand. Therefore, ALK3/BMPR-II is the BMP4/BMP2/GDF5-responsive receptor in human vascular cells, but these studies suggest that a BMP4/GDF5 selective binding protein exists in HPASMCs. These cell-specific differences in BMP responses are important for understanding the pathogenesis of FPAH.
...
PMID:Functional characterization of bone morphogenetic protein binding sites and Smad1/5 activation in human vascular cells. 1798 47

The bone morphogenetic protein (BMP) type II receptor (BMPR-II) is predominantly expressed on the vascular endothelium in the adult lung. Although mutations in BMPR-II are known to underlie many cases of familial pulmonary arterial hypertension (FPAH), little is known regarding the expression of BMPs and their signalling pathways during normal lung development or the impact of BMPR-II mutations on endothelial cell function. We determined the cellular localization and expression levels of BMP4, BMP receptors, and activation of downstream signalling via phospho-Smad1 in a developmental series of human embryonic and fetal lungs by immunohistochemistry. The expression of BMP4 and BMP receptors was temporally and spatially regulated during lung development. BMPR-II expression correlated with phosphorylation of tissue Smad1 and was highest during the late pseudoglandular and early canalicular stage of lung development, when vasculogenesis is intense. Phospho-Smad1 expression was associated with markers of proliferation in endothelial cells. In vitro studies confirmed that BMPs 2 and 4 induced phosphorylation of Smad1/5 and pulmonary artery endothelial cell (PAEC) migration and proliferation. Adenoviral transfection of PAECs with mutant kinase-deficient BMPR-II, or siRNA knockdown of BMPR-II, inhibited Smad signalling and the proliferative response to BMP4. Our findings support a critical role for BMPs in lung vasculogenesis. Dysfunctional BMP signalling in PAECs during development may lead to abnormal pulmonary vascular development and contribute to the pathogenesis of FPAH.
...
PMID:Regulation of bone morphogenetic protein signalling in human pulmonary vascular development. 1799 60

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 (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.
...
PMID:Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. 1832 66

Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor cause familial pulmonary arterial hypertension (PAH). We previously demonstrated that the substitution of cysteine residues in the ligand-binding domain of this receptor prevents receptor trafficking to the cell membrane. Here we demonstrate the potential for chemical chaperones to rescue cell-surface expression of mutant BMPR-II and restore function. HeLa cells were transiently transfected with BMPR-II wild type or mutant (C118W) receptor constructs. Immunolocalization studies confirmed the retention of the cysteine mutant receptor mainly in the endoplasmic reticulum. Co-immunoprecipitation studies of Myc-tagged BMPR-II confirmed that the cysteine-substituted ligand-binding domain mutation, C118W, is able to associate with BMP type I receptors. Furthermore, following treatment with a panel of chemical chaperones (thapsigargin, glycerol or sodium 4-phenylbutyrate), we demonstrated a marked increase in cell-surface expression of mutant C118W BMPR-II by FACS analysis and confocal microscopy. These agents also enhanced the trafficking of wild-type BMPR-II, though to a lesser extent. Increased cell-surface expression of mutant C118W BMPR-II was associated with enhanced Smad1/5 phosphorylation in response to BMPs. These findings demonstrate the potential for rescue of mutant BMPR-II function from the endoplasmic reticulum. For the C118W mutation in the ligand-binding domain of BMPR-II, cell-surface rescue leads to at least partial restoration of BMP signalling. We conclude that enhancement of cell-surface trafficking of mutant and wild-type BMPR-II may have therapeutic potential in familial PAH.
...
PMID:Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue. 1864 53

Bone morphogenetic protein receptor type 2 (BMPR2) gene mutations are a major risk factor for heritable pulmonary arterial hypertension (HPAH), an autosomal dominant fatal disease. We have previously shown that BMPR2 transcripts that contain premature termination codon (PTC) mutations are rapidly and nearly completely degraded through nonsense mediated decay (NMD). Here we report a unique PTC mutation (W13X) that did not behave in the predicted manner. We found that patient-derived cultured lymphocytes (CLs) contained readily detectable levels of the PTC-containing transcript. Further analysis suggested that this transcript escaped NMD by translational re-initiation at a downstream Kozak sequence, resulting in the omission of 173 amino acids. Treatment of CLs containing the PTC with an aminoglycoside decreased the truncated protein levels, with a reciprocal increase in full-length BMPR2 protein and, importantly, BMPR-II signaling. This is the first demonstration of aminoglycoside-mediated 'repair' of a BMPR2 mutation at the protein level in patient-derived cells and has obvious implications for treatment of HPAH where no disease-specific treatment options are available. Our data also suggest the need for a more thorough characterization of mutations prior to labeling them as haploinsufficient or dominant negative based simply on sequencing data.
...
PMID:Transcripts from a novel BMPR2 termination mutation escape nonsense mediated decay by downstream translation re-initiation: implications for treating pulmonary hypertension. 2009 88

The identification of mutations in the bone morphogenetic protein (BMP) type II receptor in the majority of cases of familial pulmonary arterial hypertension (PAH) has provided a focus for researchers studying the complex pathobiology of this condition. Mutations are also found in a proportion of idiopathic PAH cases and it is now emerging that dysfunctional BMP signaling plays a role in other more common forms of PAH, even in the absence of mutations in the gene. Study of the role of BMP signaling in endothelial, smooth muscle cell, progenitor cell and inflammatory cell biology may reveal novel pathways lending themselves to therapeutic intervention in PAH. This chapter summarizes the present status of our understanding of the role of BMPR-II mutations in PAH and indicates future directions for research.
...
PMID:Role of bone morphogenetic protein receptors in the development of pulmonary arterial hypertension. 2020 35


1 2 Next >>

---