Sex, nose and genotype.

ANNE L. CALOF GENETICS OF DISEASE Sex, nose and genotype A candidate for the gene that is deleted in Kallmann Syndrome has been identified and encodes a protein that may be of importance in the regulation of neuronal migration. Cell migration is a fundamental process in the morpho- genesis of all tissues, It plays an especially important role in neural development, where precisely timed waves of cell migration result in the formation of the functionally specialized laminae and nuclei of the central nervous sys- tem and the ganglia of the peripheral nervous system. The luteinizing hormone-releasing hormone (LHRH) sys- tem of the brain is a particularly dramatic example of the importance of cell migration in nervous system de- velopment IEIKH-expressing neurons have recently been shown to originate in a part of the developing olfactory epithelium of the nasal cavity (the vomeronasal organ), and to migrate during fetal life from their peripheral site of origin to their ftnal destinations in two nearby regions of the brain: the septal preoptic area and the hypothala- mus [1,2] (Fig. I). LHKI-I, a hypothalamic peptide which stimulates secretion of gonadotropic hormones from the anterior pituitary, is crucial for proper development and function of the male gonad. Patients suffering from the inherited disease, Kallmann Syndrome, have two distinct defects. In the X-linked form of Kallmann Syndrome, the hypogonadism that character- izes males with this syndrome seems to be the result of gonadotropin deficiency, secondary to inadequate or in- correctly regulated searetion of IHRH. This in turn has been suggested to be due to a failure of LHRH-produc- ing neurons to migrate to their hypothalamic destination during fetal development [3]. The other major defect as- sociated with Kallmann Syndrome is anosmia, or lack of the sense of smell [ 41. Odor sensation is transmitted to the brain by sensory neurons called olfactory receptor neurons, and, like the IHRI-I neurons of the hypothala- mus, these neurons are produced by the olfactory epithe- lium of the nasal cavity. Like LHRH neurons, olfactory re- ceptor neurons also penetrate the brain, but in this case their cell bodies remain in their peripheral location, while their axons enter the brain to synapse upon neurons of the olfactory bulb. The anosmia of Kallmann Syndrome is associated with agenesis of the olfactory bulbs of the brain, and experimental embryologists have shown that proper development of the olfactory bulbs requires in- nervation by olfactory receptor neurons [5]. Thus, a fail- ure of olfactory receptor neuron axons to penetrate the brain could potentially account for the lack of olfactory bulbs in Kallmann Syndrome patients [ 31. The X-linked form of Kallmann Syndrome has been mapped to the terminal part of the short arm of the X chromosome. In one study, DNA was analysed from individuals with contiguous gene syndromes (that is, complex genetic syndromes caused by deletions of contiguous genes) resulting from deletions in Xp22.3 [6]. The Kallmann Syndrome critical interval (KilL in- terval) was assigned to the region between the break- point of an X/V translocation in a patient affected by Kallmann Syndrome and four other disorders map- ping to Xp22.3 (patient AM), and the breakpoint of an X/Y translocation in a patient unaffected by Kallmann but displaying the other disorders. A subsequent study Fig. 1. Sagittal sections through the whole hea& of developing mice, show- ing migration of LHRH-expressing neu- rons (colored purple) from the devel- oping olfactory epithelium of the nasal cavity to the brain during embryonic development. (Adapted from [Il.) Volume 2 Number 2