Molecular basis of the X-chromosome-linked Kallmann's syndrome

Kallmann's syndrome combines hypogonadotropic hypogonadism and anosmia. The most frequent form of the disease is linked to the X chromosome and has been proposed to be due to a defect in the embryonic migration of GnRH neurons and olfactory axons from the nose to the brain. A candidate gene for the X-linked form of the disease has been isolated by positional cloning. Mutations in the open reading frame have been identified in several patients, providing convincing evidence that this gene is the actual gene, KAL, responsible for the X-linked Kallmann's syndrome. Correlations between molecular and clinical data extend the role of the KAL gene to other neuronal pathways and kidney organogenesis. The deduced amino acid sequence led us to postulate that the KAL protein is an extracellular matrix component with possible antiprotease and adhesion functions. Such functions are known to be involved in neuronal migration, axonal guidance and targeting, and also in synaptogenesis. Further experiments will enable the elucidation of the role of the KAL protein.