Molecular characterization of theACVRL1andENGgenes in patients with pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH; OMIM 178600) is a rare and progressive vascular disorder characterized by pulmonary vascular resistance increase, vascular remodelling and right heart failure. Approximately 75% of patients with the familial form of PAH have a mutation in BMPR2 gene. However, some other candidate genes have been advocated, including the ACVRL1 and ENG genes. These genes are located on chromosome 12q13 and on chromosome 9q33. We aimed to determine pathological changes in ACVRL1 and ENG genes presumably involved in pathology and correlate genotype/fenotype. We included 55 patients with PAH and 50 controls. The DNA extraction was performed with the Qiagen DNA kit FlexiGene. Using specifically designed primers we amplified and sequenced the exons of ACVRL1 and ENG genes. A total of 6 mutations were identified in 16% of patients for ACVRL1 gene and 4 mutations in 13% of patients for ENG gene. The mutations were not detected in a panel of 100 chromosomes from controls. 27% of patients included in this study presented any pathogenic mutation in some analysed genes. Several clinical and hemodynamics parameters showed significant differences between carriers and non-carriers of mutations, being more severe in carriers: age at diagnosis (p=0.045), mean pulmonary artery pressure (p=0.043), pulmonary vascular resistence (p=0.043) and cardiac index (p=0.04). These differences remained unchanged after adjusting for PAH type (idiopathic vs non idiopathic). The mutations detected in ACVRL1 and ENG genes indicated that these are the second most important genes implicated in the pathology. Likewise, these mutations predispose individuals to display a more severe phenotype.