Molecular basis for the Kallmann syndrome-linked fibroblast growth factor receptor mutation.

[kallmann syndrome]

Kallmann syndrome (KS ) is a developmental disease that expresses in patients as hypogonadotropic hypogonadism and anosmia . KS is commonly associated with mutations in the extracellular D 2 domain of the fibroblast growth factor receptor (FGFR ). In this study , for the first time , the molecular basis for the FGFR associated KS mutation (A 168 S ) is elucidated using a variety of biophysical experiments , including multidimensional NMR spectroscopy . Secondary and tertiary structural analysis using far UV circular dichroism , fluorescence and limited trypsin digestion assays suggest that the KS mutation induces subtle tertiary structure change in the D 2 domain of FGFR . Results of isothermal titration calorimetry experiments show the KS mutation causes a 10 -fold decrease in heparin binding affinity and also a complete loss in ligand (FGF-1 ) binding . (1 )H-(15 )N chemical perturbation data suggest that complete loss in the ligand (FGF ) binding affinity is triggered by a subtle conformational change that disrupts crucial structural interactions in both the heparin and the FGF binding sites in the D 2 domain of FGFR . The novel findings reported in this study are expected to provide valuable clues toward a complete understanding of the other genetic diseases linked to mutations in the FGFR .