Effect of Thanatophoric Dysplasia Type I Mutations on Fibroblast Growth Factor Receptor 3 Dimerization

Abstract

Thanatophoric dysplasia type I (TDI) is a lethal human skeletal growth disorder with a prevalence of 1 in 20,000 to 1 in 50,000 births. TDI is known to arise due to five different mutations, all involving the substitution of an amino acid with a cysteine in fibroblast growth factor receptor 3 (FGFR3). Cysteine mutations in receptor tyrosine kinases have been previously proposed to induce receptor cross-linking in the unliganded state, thus emulating the effect of ligand and leading to receptor overactivation. Here, we characterize the effect of three TDI mutations, Arg248Cys, Ser249Cys, and Tyr373Cys, on FGFR3 dimerization in mammalian membranes, in the absence of ligand. We demonstrate that the mutations lead to modest stabilization and structural perturbations of the FGFR3 dimers. Based on available FGFR crystal structures, we argue that the effects of these mutations cannot emulate the effect of the ligand, thus challenging the current understanding of the molecular interactions that underlie TDI.