RESUMEN
BACKGROUND: In our recent study, we first reported that mutation in vascular endothelial growth factor-A is associated with bicuspid aortic valve stenosis. However, to date no groups have explored the role of vascular endothelial growth factor-A variations in the aetiology of congenital tricuspid aortic valve stenosis. METHODS: We sequenced all eight coding exons and exon-intron boundaries of the vascular endothelial growth factor-A gene in deoxyribonucleic acid samples of a cohort of 32 sporadic patients with tricuspid aortic valve stenosis, 300 normal controls, and 103 disease controls - conotruncal defects - in order to identify sequence variants. RESULTS: We identified a c.973C > T heterozygous nonsense variation in exon 6 of the vascular endothelial growth factor-A gene in a patient with an isolated tricuspid aortic valve stenosis. The c.973C > T variation, which was absent in all controls, changes a highly conserved arginine at amino acid position 325 to a stop codon (p.Arg325X) and is predicted to produce a truncated protein of 324 amino acid residues. The proband's parents had a normal cardiac phenotype; however, his father was a carrier of the p.Arg325X variation, which indicates that the p.Arg325X variation is inherited and incompletely penetrant. CONCLUSION: We report for the first time that the p.Arg325X nonsense variation in the vascular endothelial growth factor-A gene may be associated with congenital tricuspid aortic valve stenosis.
Asunto(s)
Estenosis de la Válvula Aórtica/genética , Cardiopatías Congénitas/genética , Estenosis de la Válvula Tricúspide/genética , Factor A de Crecimiento Endotelial Vascular/genética , Adolescente , Secuencia de Aminoácidos/genética , Estenosis de la Válvula Aórtica/clasificación , Estudios de Casos y Controles , Niño , Preescolar , Exones/fisiología , Femenino , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Alineación de Secuencia , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
CHF1/Hey2 null mice generated in different laboratories have discrepant cardiovascular phenotypes. To determine the effect of genetic background on phenotype, we backcrossed our knockout strain more than eight generations to the inbred strains BALB/c and C57BL/6. Knockout mice on these backgrounds showed disparate phenotypes. Mice on both backgrounds demonstrated ventricular septal defects (VSDs), tricuspid stenosis and mitral valve thickening, but at varying frequencies, suggesting a general defect in endocardial cushion remodeling. Additional defects seen exclusively on the C57BL/6 background included biventricular wall thinning and left ventricular enlargement, implying a more severe myocardial defect than previously observed. In addition, aortas and pulmonary arteries from these null mice had thinner walls. Intercrossing of the CHF1/Hey2 null mice on a C57BL/6 background with a C57BL/6 MLC2v-CHF1/Hey2 transgenic line overexpressing CHF1/Hey2 in the atrial and ventricular myocardium also rescued the VSD and myocardial phenotypes, but did not affect vascular wall thickness. Our results indicate that CHF1/Hey2 provides an important myocardial signal to the endocardial cushion for proper septation and valve formation and also plays an important role in maturation of the myocardium and vasculature.