KDR gene variants are linked to this common congenital heart disease

Tetralogy of Fallot (TOF) is the most common type of cyanotic congenital heart disease and is generally considered to be the result of the interaction of genetic and environmental factors

It was previously discovered that the dysregulation of vascular endothelial growth factor (VEGF) signaling is related to the pathogenesis of tetralogy of Fallot, and it has been discovered that some patients have rare mutations in the gene encoding vascular endothelial growth factor receptor 2 (KDR)

An international research team led by Amsterdam University Medical Center in the Netherlands recently published an article in the journal Genetics in Medicine, reporting the role of KDR gene variants in the pathogenesis of Tetralogy of Fallot

Familial TOF cases carry KDR variants

In this study, the researchers first performed exome sequencing on a family of Moroccan descent, which had two children with severe tetralogy of Fallot (Figure 1)

The KDR gene encodes vascular endothelial growth factor receptor 2 (VEGFR2)

Afterwards, the researchers commissioned Saiye Biotech to use the CRISPR-Cas9 targeting system to generate knock-in mouse strains, each of which carried two KDR mutant mouse homologues

KDR mutations lead to decreased phosphorylation of VEGFR2

In order to clarify the biological mechanism of the two KDR mutations, the researchers then analyzed the phosphorylation of Tyrosine 1175 (Tyr1175) on VEGFR2

They used VEGF165 to stimulate HEK 293T cells that express two variants or wild-type KDR (control) heterologously

Finally, the researchers explored the pathogenic effects of KDR variants by comparing the burden of rare variants on patients with tetralogy of Fallot and controls

in conclusion

The author believes that rare KDR variants, especially protein truncation variants, are closely related to Tetralogy of Fallot and may have different inheritance patterns

Original Search

Škorić-Milosavljević, D.