Novel Mutations in BMPR2, ACVRL1 and KCNA5 Genes and Hemodynamic Parameters in Patients with Pulmonary Arterial Hypertension

Abstract

BackgroundPulmonary arterial hypertension (PAH) is a rare and progressive vascular disorder characterized by increased pulmonary vascular resistance and right heart failure. The aim of this study was to analyze the Bone Morphogenetic Protein Receptor 2 (BMPR2), Activin A type II receptor like kinase 1 (ALK1/ACVRL1) and potassium voltage-gated channel, shakerrelated subfamily, member 5 (KCNA5) genes in patients with idiopathic and associated PAH. Correlation among pathogenic mutations and clinical and functional parameters was further analyzed.Methods and ResultsForty one patients and fifty controls were included in this study. Analysis of BMPR2, ACVRL1 and KCNA5 genes was performed by polymerase chain reaction (PCR) and direct sequencing. Fifty one nucleotide changes were detected in these genes in 40 of the 41 patients; only 22 of these changes, which were classified as pathogenic, have been detected in 21 patients (51.2%). Ten patients (62.5%) with idiopathic PAH and 10 (40%) with associated PAH showed pathogenic mutations in some of the three genes. Several clinical and hemodynamics parameters showed significant differences between carriers and non-carriers of mutations, being more severe in carriers: mean pulmonary artery pressure (p = 0.043), pulmonary vascular resistence (p = 0.043), cardiac index (p = 0.04) and 6 minute walking test (p = 0.02). This differences remained unchanged after adjusting for PAH type (idiopathic vs non idiopathic).ConclusionsPathogenic mutations in BMPR2 gene are frequent in patients with idiopathic and associated PAH group I. Mutations in ACVRL1 and KCNA5 are less frequent. The presence of these mutations seems to increase the severity of the disease.

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

“…10, 22, 23 . In summary, 55 unrelated PAH patients of Spanish origin (28 IPAH, 18 APAH associated to connective tissue disease, 4 related to HIV and 5 porto-pulmonary hypertension) (Fig.…”

Novel ACLV1 Mutation Identified in Late Onset Hereditary Hemorrhagic Telangiectasia

“…The Smad dimer then enters the nucleus where it acts as a transcription factor, regulating the transcription of angiogenesis genes such as VEGF. Reduced presence of endoglin, a coreceptor for ALK family of receptors, has been shown to decrease the activity of the ALK1 pathway, as well as the ALK5 pathway that counterbalances ALK1 activity by promoting cell c.24A > T Missense p.Lys8Ans [16] c.31_50del20 Deletion p.Leu11Glyfs*20 [17] c.37delC Deletion p.Leu13Cysfs*2 [18] c.50dupT Duplication p.Leu17Phefs*21 [19] c.50_53delTGGT Deletion p.Leu*17 [20] c.61 + 1G > A Missense p.? [14] c.61 + 10G > A Splice Site p.?…”

“…[39] c.626-3C > G Splice Site p.? [55] c.632G > A Missense p.Gly211Asp [51] c.639T > G Missense p.Tyr213* [14] c.641delG Deletion p.Gly214Alafs*44 [45] c.643G > A Missense p.Glu215Lys [31] c.647T > G Missense p.Val216Gly [19] c.649T > G Missense p.Trp217Gly [45] c.650G > A Missense p.Trp217* [20] c.651G > A Missense p.Trp217* [24] c.653_654delGGinsCC Delins p.Arg218Pro [52] c.656G > A Missense p.Gly219Asp [24] c.661T > G Missense p.Trp221Gly [14] c.662G > A Missense p.Trp221* [19] c.663G > A Missense p.Trp221* [47] c.664_668delCACGG Deletion p.His222* [31] Continued c.667G > C Missense p.Gly223Arg [31] c.670G > A Missense p.Glu224Lys [25] c.673A > T Missense p.Ser225Cys [16] c.673_674delAG Deletion p.Ser225Cysfs*11 [47] c.676G > C Missense p.Val226Leu [30] c.677T > A Missense p.Val226Glu [45] c.682delG Deletion p.Val228Serfs*30 [31] c.683T > A Missense p.Val228Asp [19] c.686A > T Missense p.Lys229Met [55] c.686A > G Missense p.Lys229Arg [31] c.696_698delCTC Deletion p.Ser233del [56] c.698C > T Missense p.Ser233Leu [37] c.698C > A Missense p.Ser233* [57] c.704delA Deletion p.Asp235Valfs*23 [31] c.709C > T Missense p.Gln237* [25] c.716G > A Missense p.Trp239* [46] c.743_744delCA Deletion p.Thr248Serfs*143 [29] c.760_762delGAC Deletion p.Asp254del [18] c.759_761delCGA Deletion p.Asp254del [31] c.772 + 3_772 + 4dupAA Duplication p.? [43] c.772 + 5G > A Missense p.?…”

Pulmonary artery hypertension in childhood: The transforming growth factor-β superfamily-related genes

“…45 Patients carrying a mutation in the BMPR2, ALK1 and KCNA5 genes had a higher value of mean pulmonary pressure and pulmonary vascular resistance, and a significantly lower cardiac index than non-carriers. 47 An imbalance of increased TGF-b levels and decreased BMP signals induced by BMPR2 mutations leads to PAH. 48 The p.(S225C) mutation is located in exon 6 of ALK1 gene and it is placed in the serineethreonine kinase domain.…”