Invertebrate models of kallmann syndrome: molecular pathogenesis and new disease genes.

[kallmann syndrome]

Kallmann Syndrome is a heritable disorder characterized by congenital anosmia , hypogonadotropic hypogonadism and , less frequently , by other symptoms . The X-linked form of this syndrome is caused by mutations affecting the KAL 1 gene that codes for the extracellular protein anosmin-1 . Investigation of KAL 1 function in mice has been hampered by the fact that the murine ortholog has not been identified . Thus studies performed in other animal models have contributed significantly to an understanding of the function of KAL 1 . In this review , the main results obtained using the two invertebrate models , the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster , are illustrated and the contribution provided by them to the elucidation of the molecular pathogenesis of Kallmann Syndrome is discussed in detail . Structure-function dissection studies performed in these two animal models have shown how the different domains of anosmin-1 carry out specific functions , also suggesting a novel intramolecular regulation mechanism among the different domains of the protein . The model that emerges is one in which anosmin-1 plays different roles in different tissues , interacting with different components of the extracellular matrix . We also describe how the genetic approach in C . elegans has allowed the discovery of the genes involved in KAL 1 -heparan sulfate proteoglycans interactions and the identification of HS 6 ST 1 as a new disease gene .