Defective cellular trafficking of the bone morphogenetic protein receptor type II by mutations underlying familial pulmonary arterial hypertension

John, Anne; Kizhakkedath, Praseetha; Al‐Gazali, Lihadh; Ali, Bassam R.

doi:10.1016/j.gene.2015.02.038

Cited by 21 publications

(27 citation statements)

References 36 publications

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“…An E221V/N238I TβRII mutant found in human oral squamous cell carcinoma showed attenuated endocytosis and enhanced TGFβ signaling [112]. Mutations in the BMPR2 gene that affect the folding and subcellular trafficking of BMPR-II have been shown to be associated with pulmonary arterial hypertension [113,114].…”

Section: Tgfβ Signaling Is Controlled By Receptor Traffickingmentioning

confidence: 99%

Intracellular trafficking of transforming growth factor β receptors

Yakymovych

Heldin

2018

ABBS

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Transforming growth factor β (TGFβ) family members signal via heterotetrameric complexes of type I (TβRI) and type II (TβRII) dual specificity kinase receptors. The availability of the receptors on the cell surface is controlled by several mechanisms. Newly synthesized TβRI and TβRII are delivered from the Golgi apparatus to the cell surface via separate routes. On the cell surface, TGFβ receptors are distributed between different microdomains of the plasma membrane and can be internalized via clathrin-and caveolae-mediated endocytic mechanisms. Although receptor endocytosis is not essential for TGFβ signaling, localization of the activated receptor complexes on the early endosomes promotes TGFβ-induced Smad activation. Caveolae-mediated endocytosis, which is widely regarded as a mechanism that facilitates the degradation of TGFβ receptors, has been shown to be required for TGFβ signaling via non-Smad pathways. The importance of proper control of TGFβ receptor intracellular trafficking is emphasized by clinical data, as mislocalization of receptors has been described in connection with several human diseases. Thus, control of intracellular trafficking of the TGFβ receptors together with the regulation of their expression, posttranslational modifications and down-regulation, ensure proper regulation of TGFβ signaling.

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Section: Tgfβ Signaling Is Controlled By Receptor Traffickingmentioning

confidence: 99%

Intracellular trafficking of transforming growth factor β receptors

Yakymovych

Heldin

2018

ABBS

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“…It has been reported that not only mutations located in N-terminal or ligand binding domains, but also mutations producing a premature stop codon, could be associated with alterations in protein localization 41, 51, 52 . These aberrant proteins could be retained in the endoplasmic reticulum (ER) and activate the ER quality control (ERQC) 53, 54 . Those species retained in ER tend to dimerize with themselves and the wild-type protein, exerting a dominant negative functional effect 53, 54 .…”

Section: Discussionmentioning

confidence: 99%

“…These aberrant proteins could be retained in the endoplasmic reticulum (ER) and activate the ER quality control (ERQC) 53, 54 . Those species retained in ER tend to dimerize with themselves and the wild-type protein, exerting a dominant negative functional effect 53, 54 . The transduction signal mediated by BMPR2 also might be affected, inhibiting TGF-β pathway 55 .…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, patients carrying mutations responsible for alterations in subcellular localization, show high levels of endothelin-1 (ET-1) and reduced levels of nitric oxide (NO) 55, 58 . Down-regulation of BMPR2 stimulates the production of ET-1 and reduces the production of NO 53, 57 . For this reason, we cannot discard the idea that mutants leading to an altered subcellular localization of BMPR2 could cause an endothelial imbalance of these two genetic modifiers.…”

Section: Discussionmentioning

confidence: 99%

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Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension

Pousada

Lupo

Castro-Sánchez

et al. 2017

Sci Rep

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Pulmonary arterial hypertension is a progressive disease that causes the obstruction of precapillary pulmonary arteries and a sustained increase in pulmonary vascular resistance. The aim was to analyze functionally the variants found in the BMPR2 gene and to establish a genotype-phenotype correlation. mRNA expression studies were performed using pSPL3 vector, studies of subcellular localization were performed using pEGFP-N1 vector and luciferase assays were performed using pGL3-Basic vector. We have identified 30 variants in the BMPR2 gene in 27 of 55 patients. In 16 patients we detected pathogenic mutations. Minigene assays revealed that 6 variants (synonymous, missense) result in splicing defect. By immunofluorescence assay, we observed that 4 mutations affect the protein localization. Finally, 4 mutations located in the 5′UTR region showed a decreased transcriptional activity in luciferase assays. Genotype-phenotype correlation, revealed that patients with pathogenic mutations have a more severe phenotype (sPaP p = 0.042, 6MWT p = 0.041), a lower age at diagnosis (p = 0.040) and seemed to have worse response to phosphodiesterase-5-inhibitors (p = 0.010). Our study confirms that in vitro expression analysis is a suitable approach in order to investigate the phenotypic consequences of the nucleotide variants, especially in cases where the involved genes have a pattern of expression in tissues of difficult access.

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“…This simple hypothesis is confounded by the fact that some of these NMD− mutations, for example mis-sense mutations in the C-terminal cytoplasmic tail domain of BMPR2, may have only minor effects on BMPR2 function, 9 while others, including mis-sense and in-frame deletions in the extracellular domain of BMPR2, may have more profound effects on cellular function resulting from protein misfolding and retention in the endoplasmic reticulum (ER). [10][11][12] Despite this, there is some clinical evidence to support the hypothesis that HPAH patients with NMD− BMPR2 mutations have more severe disease than those with NMD+ mutations. Austin et al 13 evaluated disease penetrance and survival in HPAH patients in whom the NMD status was determined in cultured, patient-derived lymphoblasts.…”

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confidence: 99%

Genotype‐Phenotype Effects of Bmpr2 Mutations on Disease Severity in Mouse Models of Pulmonary Hypertension

et al. 2016

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More than 350 mutations in the type-2 BMP (bone morphogenetic protein) receptor, BMPR2, have been identified in patients with heritable pulmonary arterial hypertension (HPAH). However, only 30% of BMPR2 mutation carriers develop PAH, and we cannot predict which of these carriers will develop clinical disease. One possibility is that the nature of the BMPR2 mutation affects disease severity. This hypothesis has been difficult to test clinically, given the rarity of HPAH and the complexity of the confounding genetic and environmental risk factors. To test this hypothesis, therefore, we evaluated the susceptibility to experimental pulmonary hypertension (PH) of mice carrying different HPAH-associated Bmpr2 mutations on otherwise identical genetic backgrounds. Mice with Bmpr2ΔEx4-5 mutations (Bmpr2 +/− ), in which the mutant protein is not expressed, develop less severe PH in response to hypoxia or hypoxia with vascular endothelial growth factor receptor inhibition than mice with an extracellular-domain Bmpr2ΔEx2 mutation (Bmpr2 ΔEx2/+ ), in which the mutant protein is expressed. This was associated with a marked decrease in stabilizing phosphorylation of threonine 495 endothelial nitric oxide synthase (pThr495 eNOS) in Bmpr2ΔEx2/+ compared to wild-type and Bmpr2 +/− mouse lungs. These findings provide the first experimental evidence that BMPR2 mutation types influence the severity of HPAH and suggest that patients with BMPR2 mutations who express mutant BMPR2 proteins by escaping non-sense-mediated messenger RNA decay (NMD− mutations) will develop more severe disease than HPAH patients with NMD+ mutations who do not express BMPR2 mutant proteins. Since decreased levels of pThr495 eNOS are associated with increased eNOS uncoupling, our data also suggest that this effect may result from defects in eNOS function.Keywords: bone morphogenetic protein type 2 receptor mutations, experimental pulmonary hypertension, hereditary pulmonary arterial hypertension, disease severity, non-sense-mediated messenger RNA decay, endothelial nitric oxide synthase. Patients with heritable pulmonary arterial hypertension (HPAH) inherit heterozygous mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2) locus.1 BMPR2 mutations account for about 75% of patients with family histories of PAH and 25% of patients with sporadic disease. This establishes BMPR2 mutations as the major genetic determinant of HPAH. 2 BMPR2 mutation carriers with PAH tend to have an earlier age of diagnosis and more severe pulmonary hemodynamic parameters and are less likely to demonstrate vasoreactivity than noncarriers. 3-6 However, less than 30% of BMPR2 mutation carriers develop clinical disease, 7 and while the disease is known to have a sex bias and a number of candidate disease-modifying genetic variants at other loci have been shown to influence disease penetrance, 2 we are still unable to predict which patients carrying BMPR2 mutations will develop overt disease or, if they do, how severe their disease will be. One possibility is ...

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Defective cellular trafficking of the bone morphogenetic protein receptor type II by mutations underlying familial pulmonary arterial hypertension

Cited by 21 publications

References 36 publications

Intracellular trafficking of transforming growth factor β receptors

Intracellular trafficking of transforming growth factor β receptors

Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension

Genotype‐Phenotype Effects of Bmpr2 Mutations on Disease Severity in Mouse Models of Pulmonary Hypertension

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Defective cellular trafficking of the bone morphogenetic protein receptor type II by mutations underlying familial pulmonary arterial hypertension

Cited by 21 publications

References 36 publications

Intracellular trafficking of transforming growth factor &beta; receptors

Intracellular trafficking of transforming growth factor &beta; receptors

Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension

Genotype‐Phenotype Effects of Bmpr2 Mutations on Disease Severity in Mouse Models of Pulmonary Hypertension

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Intracellular trafficking of transforming growth factor β receptors

Intracellular trafficking of transforming growth factor β receptors