Abstract
Pulmonary Arterial Hypertension (PAH; OMIM 178600, ORPHA 422) is an autosomal dominant disease characterized by pulmonary vascular resistance increase, vascular remodelling and right heart failure. Symptoms of PAH include fatigue, shortness of breath and syncope. However, the result of missense, nonsense, synonymous and 5´UTR region mutations in BMPR2 gene is unknown. The aims were to determine pathological changes in BMPR2 gene presumably involved in an erroneous processing of mRNA, check the subcellular localization of missense and nonsense variats and correlate genotype/fenotype.
Variants were selected from an in silico analysis. mRNA expression studies were performed using pSPL3 vector to confirm splicing alterations and studies of subcellular localization were performed using pEGFP-N1 vector. Correlation genotype-phenotype was performed using Spss v.19 software.
Nine out of 24 changes analyzed were observed to affect mRNA processing (p.S52Sfs*2, p.C84F, p.P138A, p.R211R, p.Y218*, p.V278V, p.W298*, p.P327P, p.K467R). These changes produced either exon skipping or removed the main donor or acceptor sites to create a new donor or acceptor splice-site. Four out of 18 variants analyzed altered the subcellular localization of BMPR2 protein (p.S52Sfs*2, p.C84F, p.Y218*, W298*). Patients with these pathogenic mutations had a lower age of diagnosis (p=0.047) and greater sPaP (p=0.042).
Functional and molecular studies have allowed us to check the real implication of the mutations studied and correlate the role in the phisiopathological pathway of the disease. Likewise, these mutations predispose individuals to a more severe phenotype and this group of patients showed an early age at diagnosis.
- Copyright ©ERS 2015