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Sci Rep. 2017 May 15;7(1):1923. doi: 10.1038/s41598-017-02074-8.

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

Author information

1
Dep. Biochemistry, Genetics and Immunology. Faculty of Biology, University of Vigo, As Lagoas Marcosende S/N, 36310, Vigo, Spain.
2
Grupo de Investigación Enfermedades Raras y Medicina Pediátrica, Instituto de Investigación Sanitaria Galicia Sur (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain.
3
Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigación Príncipe Felipe (CIPF), 46012, Valencia, Spain.
4
Neumology Service, Complexo Hospitalario Universitario de Pontevedra, 36071, Pontevedra, Spain.
5
Dep. Biochemistry, Genetics and Immunology. Faculty of Biology, University of Vigo, As Lagoas Marcosende S/N, 36310, Vigo, Spain. dianaval@uvigo.es.
6
Grupo de Investigación Enfermedades Raras y Medicina Pediátrica, Instituto de Investigación Sanitaria Galicia Sur (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain. dianaval@uvigo.es.

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.

PMID:
28507310
PMCID:
PMC5432510
DOI:
10.1038/s41598-017-02074-8
[Indexed for MEDLINE]
Free PMC Article

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