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

Scientific Reports
Guillermo PousadaDiana Valverde

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 appr...Continue Reading

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Citations

Dec 22, 2017·Journal of Cellular and Molecular Medicine·Guillermo PousadaDiana Valverde
Mar 19, 2021·The Application of Clinical Genetics·Emmanuel Eroume-A EgomRene Kamgang
Mar 23, 2021·Nature Communications·David S M LeeYoseph Barash

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Methods Mentioned

BETA
electrophoresis
PCR
Assay
transfection

Software Mentioned

MutationTaster2
SPSS
PolyPhen
Sift
Ensembl
MatInspector
Pmut
NetGene2 View
NNSplice
Human Splice Finder ( HSF

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