Recurrent platelet-derived growth factor receptor beta gene mutations in Kosaki overgrowth syndrome: a molecular and clinical overview

Objective Kosaki overgrowth syndrome (KOGS) is a rare genetic disorder linked to germline variants in the platelet-derived growth factor receptor beta gene ( PDGFRB ) that is characterized by postnatal overgrowth, hyperelastic skin, lipodystrophy, and craniofacial anomalies. This study aimed to summarize clinical and genetic data from reported KOGS cases and investigate the molecular consequences of two recurrent KOGS-associated PDGFRB variants. Methods Clinical and genetic information from 17 previously published KOGS cases was reviewed. Molecular studies were performed using patient-derived fibroblasts and genetically modified cells transduced with the recurrent PDGFRB variants Trp566Arg and Pro584Arg. Downstream signaling and phosphorylation of PDGFRB tyrosine residues were assessed by immunoblotting and immunocytochemistry. Results Both variants induced phosphorylation of specific PDGFRB tyrosine residues and activated downstream signaling pathways in the absence of ligand stimulation, which could contribute to the phenotypic overgrowth observed in KOGS. Immunocytochemistry revealed vesicle-like structures of phosphorylated PDGFRB (pY740), resembling wild-type cells stimulated with growth factor, thereby supporting the constitutive activation of PDGFRB in patient fibroblasts. Both variants showed sensitivity to the tyrosine kinase inhibitor imatinib. Conclusions Recurrent PDGFRB variants in KOGS cause ligand-independent activation of PDGFRB , contributing to the overgrowth phenotype. Imatinib may represent a potential targeted therapeutic option.