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 5
The R470L FGFR1 mutation is loss-of-function. (A) The R→L substitution abolishes hydrogen bonds that play a role in the positioning of the C-helix of FGFR1. The unphosphorylated “low-activity” form of the FGFR1 kinase domain (PDB ID: 1FGK) is represented as a ribbon diagram. The N-lobe of the FGFR1 kinase is shown in green, with the exception of the αC helix, which is in blue. Red: C-lobe of FGFR1 kinase; gray: linker connecting the N- and C-lobes; yellow: activation loop in the C-lobe. Selected residues are shown, and hydrogen bonds are represented as dashed lines. R470 indirectly contributes to the proper positioning of αC in the kinase domain and hence kinase regulation by engaging in 3 hydrogen bonds with D468, which in turn engages in a hydrogen bond with K536 from αC helix. (B) The R470L mutation reduces the tyrosine kinase activity of FGFR1.