Corneal neovascularization associated with a novel PDGFRB gene variant: Implications for precision medicine treatment

Abstract

AbstractPurpose: To identify the genetic cause of aggressive corneal neovascularization arising in otherwise healthy children in one family. Further, to study molecular consequences associated with the identified variant and implications for possible precision medicine treatment.Methods: Sanger sequencing of the candidate gene PDGFRB was performed in affected individuals. HeLa cells were transduced with wild type PDGFRB and the identified variant. Cells were treated with tyrosine kinase inhibitors (TKIs). ELISA and immunoblot analysis were used to detect phosphorylation of PDGFRβ and downstream signalling proteins.Results: A novel variant in PDGFRB was found in affected family members. HeLa cells transduced with this variant did not have increased baseline levels of phosphorylated PDGFRb. However, upon stimulation with ligand, excessive activation of PDGFRb was observed in these cells compared to cells transduced with the wild type variant. Inhibition with some TKIs in vitro successfully prevented upregulation of PDGFRβ and its downstream signalling.Conclusions: A novel substitution in PDGFRB was found in family members with isolated corneal neovascular overgrowth. Cells transduced with the variant showed increased phosphorylation upon ligand stimulation. While the examined TKIs had various effects in preventing such overactivation, this introduces the concept of precision medicine in preventing childhood blindness in these patients.