The Kallmann syndrome gene product expressed in COS cells is cleaved on the cell surface to yield a diffusible component

Kallmann syndrome is characterized by hypogonadotropic hypogonadism andanosmia and caused by a defect of migration and targeting ofgonadotropin-releasing hormone-secreting neurons and olfactory axons duringembryonic development. We previously cloned the gene responsible for theX-linked form of the disease encoding a 680 amino acid protein, KAL, whichdisplays the unusual combination of a protease inhibitor domain withfibronectin type III repeats. Previous expression studies by northern blotand RNA in situ hybridization in human and chick indicated that the gene isexpressed at very low levels in the olfactory bulb during development.Therefore, low abundance of the protein has hampered a detailed biochemicalcharacterization. By overexpressing both the human and chick KAL cDNAs ineukaryotic cells, we now provide evidence that KAL is a glycosylatedperipheral membrane protein with an apparent molecular weight ofapproximately 100 kDa. We show that this 100 kDa protein is proteolyticallyprocessed on the cell membrane to yield a 45 kDa diffusible component,which is detectable with an antisera against the C-terminal part of theprotein and binds tightly to cell surfaces. These data provide a first steptoward understanding KAL function in neuronal interactions and neuriteextension in the olfactory bulb and suggest that KAL might be a diffusiblechemoattractant molecule for olfactory axons.