Endocrine Abstracts

The defining features of Kallmann's syndrome (KS) are isolated hypogonadotrophic hypogonadism (IHH) and anosmia, the consequences of a GnRH neuronal migratory defect and olfactory bulb agenesis respectively. Additional features in X-linked Kallmann's syndrome (XKI), include unilateral renal agenesis and bimanual synkinesis respectively. XKI results from mutations of KALIG 1, on Xp22.3. The encoded protein anosmin-1, is a hexamodular secreted cell membrane associated extracellular matrix protein comprising a cysteine rich N-terminus, a WAP type domain followed by four consecutive fibronectin type III domains. Anosmin-1 is expressed in the developing olfactory bulb, but also in the forebrain, the neuroretina (amacrine cells), developing spinal cord (sulcus limitans) and metanephric blastema. There is considerable interspecies conservation of anosmin-1, with orthologues in zebrafish, chicken, quail, C Elegans and Drosophila Melanogaster (Dm) where anosmin-1 is expressed within the central projections of the antennal system. Anosmin-1 , particularly its first fibronectin module, is strongly associated with cell membrane and extracellular matrix heparan sulphate (HS) proteoglycans, with which it has < 10 nM affinity.The importance of this interaction in underlined by the observation that absence of heparan-6-0-sulphotransferase in C Elegans virtually abolishes CeKal-1 overexpression-induced phenotype. In vitro studies support a role of anosmin-1 in axonal branching, and anosmin-1 induces axon outgrowth from human GnRH producing FNCB-4 primary cell cultures of olfactory placodal origin. Anosmin-1 may interact with urokinase plasminogen activator (UPA) within the developing bulb, and has been shown to stimulate proliferation of prostatic carcinoma (PC-3) cells. In-vitro studies also show that it modulates UPA's amidolytic activity. Recently, FGFR1 receptor mutations have been shown to be associated with the autosomal dominant form of KS , and it is has been proposed that anosmin-1 may interact with the FGFR1-FGF2-HS complex to modulate signal transduction.