Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism
J. Clin. Invest. Nelly Pitteloud, et al. 117:457 doi:10.1172/JCI29884 [Go to this article.]

Figure 3
The L342S mutation dramatically reduces affinity of FGFR1c for FGF8b, implicating decreased FGF8b/FGFR1c signaling in the etiology of KS/IHH. (A–F) The L342S mutation reduces the affinity of FGFR1c for FGF8b. Varying concentrations of WT (A–C) or L342S FGFR1c mutant (D–F) were injected over a CM5 chip onto which FGF1 (A and D), FGF2 (B and E), and FGF8b (C and F) were immobilized. Analyte concentrations are indicated as follows: 31.25 nM in gray, 62.5 nM in violet, 125 nM in green, 250 nM in red, 500 nM in blue. (G) The location of L343 in FGFR2c, the residue corresponding to L342 in FGFR1c, is mapped onto the FGF8b-FGFR2c structure (18). The L342S mutation should weaken key hydrophobic contacts between F32, V36, and F93 of FGF8b and D3 of FGFR. Gray: molecular surface of FGFR; orange: FGF8b. The side chains of selected residues are shown. The molecular surface of the hydrophobic groove of FGFR D3 (yellow) is rendered transparent so that the side chain of L343 (the residue corresponding to L342 of FGFR1c) is visible. (H) L342S FGFR1 heterozygous mutation is a loss-of-function mutation. WT and L342S FGFR1c were transiently transfected into L6 myoblasts with an FGFR1-responsive osteocalcin promoter luciferase construct. FGF8b treatment of WT FGFR1c induced a 6-fold increase in LUC reporter gene expression, while the L342S FGFR1c alone remained silent. The coexpression of the WT and L342S FGFR1c suggests that this mutation acts as a dominant negative.