X-linked GnRH deficiency: Role of KAL-1 mutations in GnRH deficiency

The gene for X-linked Kallmann’s syndrome (KAL-1, encoding anosmin-1) was cloned in 1991. Over a decade elapsed before autosomal forms of KS and most of other genetic forms of isolated hypogonadotrophic hypogonadism (IHH) became characterized, and the genetic diversity of these disorders fully appreciated. Although KAL-1 mutations appear to cause a more severe reproductive phenotype than other IHH genes, the biology of this multidomain extracellular matrix protein has only been partially characterized. Initial studies suggested a central role of anosmin-1, in GnRH neuron ontogeny – specifically in GnRH neuronal migration from the cribriform plate area into the brain – as well as in olfactory bulb development. Anosmin-1 is expressed extracellularly, with high affinity binding to cell membrane heparan sulphate proteoglycans. It is expressed in the outer layers of the developing olfactory bulb, the neuroretina, the cerebellum, spinal cord and developing kidney. Recent observations have demonstrated an anosmin-1 heparan sulphate dependent functional interaction with the product of the autosomal dominant KAL-2 (FGFR1: anosmin-2) gene, thereby modulating FGFR1 signalling. Although these genes are frequently co-expressed in developing tissues, this may not represent the sole mode of action of anosmin-1, and FGFR1 independent actions of the protein have also been identified. Structural and in vitro functional studies have shown that anosmin-1 may have complex biological actions. Anosmin-1 interactions with FGFR1 have however been best characterized and represent the dominant focus of this chapter.