CAENORHABDITIS ELEGANS AS AN ANIMAL MODEL FOR X-LINKED KALLMANN SYNDROME

Kallmann Syndrome (KS) is a genetic disease characterized by anosmia and hypogonadism. Three familial forms are known and the X-linked one is the most frequent. The human gene responsible for the X-linked form of the disease has been identified. Very little is known about the mechanism of action of its product, the protein KAL, at the molecular and cellular level. Studies in chicken and humans have indicated that KAL, is produced by the olfactory bulbs and is necessary for the innervation and organization of the bulbs. So far it has not been possible to obtain mice mutants for this gene as animal models for this genetic condition because the mouse homolog gene has not been identified. We have focused on a gene of the nematode Caenorhabditis elegans, kal-1, which is the homolog of the human gene. The structure of the nematode gene, the cells that express it and the phenotypes of mutants have been determined. We have shown that the human gene can compensate for the loss of the nematode one. Our studies provide a unique animal model in which the function of a Kal gene can be studied in an organism amenable to genetic and molecular analysis of development. The aims of the program are: to understand the function of KAL-1; to identify other molecules with which it interacts, and to elucidate some aspects of the biochemical properties of KAL proteins. The long term objectives of the project are: a) an understanding of KAL function at the molecular and cellular level detailed enough to be useful to explain the pathogenesis of all the symptoms of the disease; b) the identification of the genes responsible for the other genetic forms of Kallmann Syndrome. These long term objectives would be relevant from a health care point of view as they can provide diagnostic tools for the non-X-linked form of KS and suggest new ideas and strategies for the management of all the clinical symptoms of KS patients as well as of patients with other neurological disorders.