Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice

Abstract

Idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (Kallmann syndrome; KS) or with a normal sense of smell (normosmic IHH; nIHH) are heterogeneous genetic disorders associated with deficiency of gonadotropin-releasing hormone (GnRH). While loss-of-function mutations in FGF receptor 1 (FGFR1) cause human GnRH deficiency, to date no specific ligand for FGFR1 has been identified in GnRH neuron ontogeny. Using a candidate gene approach, we identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes. These patients exhibited varied degrees of GnRH deficiency, including the rare adultonset form of hypogonadotropic hypogonadism. Four mutations affected all 4 FGF8 splice isoforms (FGF8a, FGF8b, FGF8e, and FGF8f), while 2 mutations affected FGF8e and FGF8f isoforms only. The mutant FGF8b and FGF8f ligands exhibited decreased biological activity in vitro. Furthermore, mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. In conclusion, we identified FGF8 as a gene implicated in GnRH deficiency in both humans and mice and demonstrated an exquisite sensitivity of GnRH neuron development to reductions in FGF8 signaling.

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…Genes encoding fibroblast growth factor 8 (FGF8) signalling pathway proteins, [17][18][19][20][21][22] chromodomain helicase DNA-binding protein 7 (CHD7) [23][24][25][26][27] and sex determining region Y-Box 10 (SOX10) 28,29 affect the neurogenic niche in the nasal area and craniofacial development. Conversely, Kallmann syndrome protein, which is now officially known as anosmin 1 (encoded by KAL1; following nomenclature change, the gene is now denoted as ANOS1), 2 prokineticin-2 and prokineticin receptor 2 (encoded by PROK2 and PROKR2, respectively), [30][31][32][33] WD repeat domain 11 (encoded by WDR11), 34,35 semaphorin 3A (encoded by SEMA3A) [36][37][38] and FEZ family zinc finger 1 (encoded by FEZF1) 39 influence migration of GnRH neurons.…”

“…117,118 To date, >25 different genes have been implicated in Kallmann syndrome and/or CHH, which accounts for ~50% of cases. 21 Causative genes for Kallmann syndrome include: KAL1 (ANOS1) in the X-linked form; FGFR1 (encoding fibroblast growth factor receptor 1), 17,18 FGF8, 19,119 CHD7, [23][24][25][26][27] HS6ST1 (encoding heparan-sulphate 6-O-sulphotransferase 1), 20 SOX10, 28,29 SEMA3A (encoding semaphorin-3A), [36][37][38] WDR11 (encoding WD repeat-containing protein 11) 34,35 and IL17RD (encoding interleukin-17 receptor D) 21 in the autosomal dominant form; and PROKR2 and/or PROK2, [30][31][32][33] and FEZF1 39 in the autosomal recessive form, even though it should be noted that most patients carrying mutations in PROKR2 or PROK2 carry these mutations in the heterozygous state. 120,121 Genes involved in CHH that are associated with a normal sense of smell include GNRHR (encoding gonadotropinreleasing hormone receptor), 122,123 GNRH1 (encoding gonadotropin-releasing hormone 1), 124,125 KISS1R, 41,42 KISS1, 40,126 TACR3 and TAC3.…”

Kallmann syndrome

“…5,61 Five causal genes have been identified to date, namely, by chronological order of discovery, KAL1, 62 -64 FGFR1, 7 PROKR2 and PROK2, 10 and FGF8. 65 Various loss-of-function mutations in KAL1, encoding the extracellular matrix glycoprotein anosmin-1, and in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, underlie the X chromosome-linked form (KAL1) and an autosomal dominant form (KAL2) of KS, respectively (see Supplementary Tables S1, S2 and S3 for a list of the mutations). The KAL1 and KAL2 genetic forms account for roughly 8% and 10% of all KS cases, respectively.…”

“…On the other hand, the loss of nasal cartilage, external ear hypoplasia, and skeletal anomalies of the hands or feet, have only been reported in KAL2 patients. 7,13,48 By contrast, hearing impairment is common to several genetic forms of KS, 7,8,13,23,24,29,65 although it should be noted that the underlying defect (conductive, perceptive, or mixed) is likely to vary between different genetic forms. Palate defects should also be considered as one of these shared traits, even though the severity differs between KAL1 (high arched palate) and KAL2 (cleft palate).…”

“…In Prokr2 or Prok2 homozygous knockout mice, and mice carrying Fgfr1 or Fgf8 hypomorphic mutations in the homozygous state, however, the migration of these cells is disrupted too. 14,65,79,80 The mechanism of the putative defect of GnRH cell migration in KS is still conjectural. It could be either a consequence of the early degeneration of olfactory nerve and terminal nerve axons, which act as guiding cues, or a process directly affecting the GnRH cells themselves.…”