Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension
Abstract 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 c...
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2017
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oai:doaj.org-article:6b58ee7f72ba4e7fbad01dfe022de7482021-12-02T11:52:29ZMolecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension10.1038/s41598-017-02074-82045-2322https://doaj.org/article/6b58ee7f72ba4e7fbad01dfe022de7482017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02074-8https://doaj.org/toc/2045-2322Abstract 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.Guillermo PousadaVincenzo LupoSheila Cástro-SánchezMaría Álvarez-SattaAna Sánchez-MonteagudoAdolfo BaloiraCarmen EspinósDiana ValverdeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-19 (2017) |
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Medicine R Science Q Guillermo Pousada Vincenzo Lupo Sheila Cástro-Sánchez María Álvarez-Satta Ana Sánchez-Monteagudo Adolfo Baloira Carmen Espinós Diana Valverde Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension |
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Abstract 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. |
format |
article |
author |
Guillermo Pousada Vincenzo Lupo Sheila Cástro-Sánchez María Álvarez-Satta Ana Sánchez-Monteagudo Adolfo Baloira Carmen Espinós Diana Valverde |
author_facet |
Guillermo Pousada Vincenzo Lupo Sheila Cástro-Sánchez María Álvarez-Satta Ana Sánchez-Monteagudo Adolfo Baloira Carmen Espinós Diana Valverde |
author_sort |
Guillermo Pousada |
title |
Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension |
title_short |
Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension |
title_full |
Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension |
title_fullStr |
Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension |
title_full_unstemmed |
Molecular and functional characterization of the BMPR2 gene in Pulmonary Arterial Hypertension |
title_sort |
molecular and functional characterization of the bmpr2 gene in pulmonary arterial hypertension |
publisher |
Nature Portfolio |
publishDate |
2017 |
url |
https://doaj.org/article/6b58ee7f72ba4e7fbad01dfe022de748 |
work_keys_str_mv |
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