Novel insights in FGFR1 regulation: lessons from Kallmann syndrome.

Disrupted fibroblast growth factor receptor (FGFR)1 signalling has been shown to cause Kallmann syndrome (KS), a human genetic disorder characterised by olfactory bulb dysgenesis and hypogonadotrophic hypogonadism. Loss-of-function mutations in the KS gene KAL-2/FGFR1 account for roughly 10% of KS cases, leading to the autosomal dominant form of the disease. Anosmin-1, the KAL-1 gene product underlying X-linked KS, modulates FGFR1 signalling via regulation of FGF2/FGFR1/heparin signalling complex assembly and activity. This review covers recent advances in the potential interactions of KS-associated molecules within the FGFR1 signalling complex, and demonstrates a novel mechanism of pre-signalling modulation that mechanistically links an autosomal dominant and sex-linked mode of inheritance of this disease, highlighting the central role of FGFR1 signalling in KS. Copyright (c) 2010 Elsevier Ltd. All rights reserved.