The cysteine-rich region and the whey acidic protein domain are essential for anosmin-1 biological functions.

[kallmann syndrome]

The protein anosmin-1 , coded by the KAL 1 gene responsible for the X-linked form of Kallmann syndrome (KS ), exerts its biological effects mainly through the interaction with and signal modulation of fibroblast growth factor receptor 1 (FGFR 1 ). We have previously shown the interaction of the third fibronectin-like type 3 (FnIII ) domain and the N-terminal region of anosmin-1 with FGFR 1 . Here , we demonstrate that missense mutations reported in patients with KS , C 172 R and N 267 K did not alter or substantially reduce , respectively , the binding to FGFR 1 . These substitutions annulled the chemoattraction of the full-length protein over subventricular zone (SVZ ) neuronal precursors (NPs ), but they did not annul it in the N-terminal-truncated protein (A 1 Nt ). We also show that although not essential for binding to FGFR 1 , the cysteine-rich (CR ) region is necessary for anosmin-1 function and that FnIII .3 can not substitute for FnIII .1 function . Truncated proteins recapitulating nonsense mutations found in KS patients did not show the chemotropic effect on SVZ NPs , suggesting that the presence behind FnIII .1 of any part of anosmin-1 produces an unstable protein incapable of action . We also identify the extracellular signal-regulated kinase 1 /2 (ERK 1 /2 ) pathway as necessary for the chemotropic effect exerted by FGF 2 and anosmin-1 on rat SVZ NPs .