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FGFR1, FGF8, PROKR2, PROK2, ANOS1, and the Olfactogenital (Kallmann) Syndrome 

FGFR1, FGF8, PROKR2, PROK2, ANOS1, and the Olfactogenital (Kallmann) Syndrome
FGFR1, FGF8, PROKR2, PROK2, ANOS1, and the Olfactogenital (Kallmann) Syndrome

Jean-Pierre Hardelin

and Catherine Dodé

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date: 07 March 2021

Kallmann syndrome (KS) combines hypogonadotropic hypogonadism with anosmia related to an absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism results from gonadotropin-releasing hormone (GnRH) deficiency. The prevalence of KS is higher in males than in females. Patients usually present with an absence of spontaneous puberty. However, some patients undergo partial puberty and others are even spontaneously fertile. The degree of smell impairment also differs between individuals with KS, from mild hyposmia to anosmia, even within a single family. KS is genetically heterogeneous, with several different modes of transmission: X chromosome-linked, autosomal dominant, autosomal recessive and presumably oligogenic. To date, loss-of-function mutations in any of ten causal genes—KAL1 (Kallmann syndrome 1), FGFR1 (fibroblast growth factor receptor 1), FGF8 (fibroblast growth factor 8), PROKR2 (prokineticin receptor 2), PROK2 (prokineticin 2), HS6ST1 (heparan sulfate 6-O-sulfotransferase 1), WDR11 (WD repeat domain 11), SEMA3A (semaphorin 3A), SOX10 (sex determining region Y-box 10), CHD7 (chromodomain helicase DNA-binding protein 7)—have been found in approximately 30% of KS patients. This chapter focuses on the first five of these genes, which encode proteins involved in two well defined cell signaling systems: FGF signaling and prokineticin signaling. Mutations of FGFR1 or FGF8 underlie an autosomal dominant form of the disease (KAL2) with incomplete penetrance. Mutations of PROKR2 or PROK2 underlie an autosomal recessive form of the disease (KAL3), but the mutations are mostly found in the heterozygous state, raising questions about the possible digenic/oligogenic inheritance of KS, which has been confirmed in a few patients. Finally, KAL1 mutations are responsible for the X-chromosome-linked form of the disease (KAL1). KAL1 encodes anosmin-1, a secreted glycoprotein that is present locally in various extracellular matrices during organogenesis. Anosmin-1 is thought to enhance fibroblast growth factor (FGF) signaling and, perhaps, prokineticin signaling too. Other KS genes remain to be identified, some of which might also be involved in FGF signaling or prokineticin signaling. The pathogenesis of the disorder of olfactory development in KS is not fully understood and may involve a primary failure of olfactory axon terminal elongation or targeting, but also a morphogenetic defect of the olfactory bulbs and a defect in the axonal branching of the olfactory bulb output neurons. In the late 1980s, new light was shed on the mechanism of GnRH deficiency, with the discovery of a close topographic link between the peripheral olfactory system and neuroendocrine GnRH cells during embryonic development. In all vertebrates studied to date, these cells migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway. Pathohistological analysis of arhinencephalic human fetuses (i.e. with olfactory bulb agenesis) with X chromosome-linked KS, CHARGE syndrome, trisomy 13 or trisomy 18 has shown interrupted olfactory nerve fibers forming bilateral neuromas in the frontonasal region, together with an accumulation of GnRH cells not penetrating into the brain. These observations define the olfactogenital fetopathological sequence whereby the incomplete embryonic migration of neuroendocrine GnRH cells, leading to hypogonadotropic hypogonadism, arises from the primary failure of peripheral olfactory structures. This sequence may occur alone, resulting in isolated KS, or together with various nonolfactory and nonreproductive developmental disorders, depending on the genetic defects involved. In the KAL2 genetic form of KS, caused by mutations of FGFR1 or FGF8, however, defects in the fate specification of GnRH cells and/or a failure of these cells to emerge from the nasal pit described in mouse models would be expected to mask any disruption of the subsequent migratory pathway. Molecular structures and bioactivities of the FGFR1, FGF8, PROKR2, PROK2 and KAL1 proteins

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