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 an d anosmia and caused by a defect of migration and targeting of gonadot ropin-releasing hormone-secreting neurons and olfactory axons during e mbryonic development. We previously cloned the gene responsible for th e X-linked form of the disease encoding a 680 amino acid protein, KAL, which displays the unusual combination of a protease inhibitor domain with fibronectin type III repeats, Previous expression studies by nor thern blot and RNA in situ hybridization in human and chick indicated that the gene is expressed at very low levels in the olfactory bulb du ring development, Therefore, low abundance of the protein has hampered a detailed biochemical characterization. By overexpressing both the h uman and chick KAL cDNAs in eukaryotic cells, we now provide evidence that KAL is a glycosylated peripheral membrane protein with an apparen t molecular weight of approximately 100 kDa. We show that this 100 kDa protein is proteolytically processed on the cell membrane to yield a 45 kDa diffusible component, which is detectable with an antisera agai nst the C-terminal part of the protein and binds tightly to cell surfa ces, These data provide a first step toward understanding KAL function in neuronal interactions and neurite extension in the olfactory bulb and suggest that KAL might be a diffusible chemoattractant molecule fo r olfactory axons.