HGNC Approved Gene Symbol: FGF17
Cytogenetic location: 8p21.3 Genomic coordinates (GRCh38) : 8:22,039,672-22,048,809 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p21.3 | Hypogonadotropic hypogonadism 20 with or without anosmia | 615270 | Autosomal dominant | 3 |
Fibroblast growth factors (FGFs), such as FGF17, are growth factors and oncogenes that contain a conserved, approximately 120-amino acid core. Individual FGFs play important roles in embryonic development, cell growth, morphogenesis, tissue repair, inflammation, angiogenesis, and tumor growth and invasion (Hoshikawa et al., 1998).
Hoshikawa et al. (1998) isolated human, mouse, and rat cDNAs encoding a novel member of the FGF family, FGF17. The deduced 216-amino acid human FGF17 protein is 98.6% identical to the mouse and rat Fgf17 proteins, which are identical. Among known FGF family members, the FGF17 protein is most similar to FGF8 (600483). FGF17 contains a typical hydrophobic signal sequence at its N terminus, and the authors demonstrated that recombinant rat Fgf17 can be efficiently secreted by High Five insect cells. PCR analysis of rat adult tissues detected Fgf17 expression in all tissues examined. In rat 14.5-day embryos, in situ hybridization showed highest Fgf17 expression in the isthmus cerebellar and septum neuroepithelia of the brain.
Using RT-PCR, Krejci et al. (2007) detected expression of several FGF genes in femoral growth plate cartilage from 20- to 28-week gestation fetuses; however, only FGF1 (131220), FGF2 (134920), FGF17, and FGF19 (603891) proteins were expressed at detectable levels. Immunohistochemical analysis showed that FGF17 and FGF19 were uniformly expressed throughout the growth plate. In contrast, FGF1 was expressed only in the proliferative and hypertrophic zones, and FGF2 was expressed only in the proliferative and resting zones.
To link FGF17 to GnRH (see 152760) biology, Miraoui et al. (2013) examined Fgf17 expression in the nasal cavity of mouse embryos at embryonic day 10.5, when GnRH neuron fate specification occurs. Fgf17 was robustly expressed in regions where Fgf8 is known to be highly expressed: the commissural plate, the midbrain-hindbrain junction, and the medial olfactory placode, where GnRH neurons emerge. Miraoui et al. (2013) noted that there was hardly any Fgf17 expression in Fgf8 hypomorphic mice, suggesting that FGF17 should be considered a member of the FGF8 synexpression group.
Using the Cre/loxP system, Sun et al. (2000) found that maintenance of Fgf9 (600921) and Fgf17 expression is dependent on Shh (600725), whereas Fgf8 expression is not. Sun et al. (2000) developed a model in which no individual Fgf expressed in the apical ectodermal ridge is solely necessary to maintain Shh expression, but instead the combined activity of 2 or more apical ectodermal ridge Fgfs function in a positive feedback loop with Shh to control limb development.
Krejci et al. (2007) showed that FGF1, FGF2, and FGF17, but not FGF19, elicited potent activation of an ERK (see 601795) reporter gene in primary cultures of human fetal chondrocytes. FGF1, FGF2, and FGF17, but not FGF19, also inhibited proliferation of FGFR3 (134934)-expressing rat chondrosarcoma chondrocytes.
Mariani et al. (2008) demonstrated that mouse limbs lacking Fgf4 (164980), Fgf9, and Fgf17 have normal skeletal pattern, indicating that Fgf8 (600483) is sufficient among apical ectodermal ridge fibroblast growth factors (AER-FGFs) to sustain normal limb formation. Inactivation of Fgf8 alone causes a mild skeletal phenotype; however, when Mariani et al. (2008) also removed different combinations of the other AER-FGF genes, they obtained unexpected skeletal phenotypes of increasing severity, reflecting the contribution that each FGF can make to the total AER-FGF signal. Analysis of the compound mutant limb buds revealed that, in addition to sustaining cell survival, AER-FGFs regulate proximal-distal patterning gene expression during early limb bud development, providing genetic evidence that AER-FGFs function to specify a distal domain and challenging the longstanding hypothesis that AER-FGF signaling is permissive rather than instructive for limb patterning. Mariani et al. (2008) also developed a 2-signal model for proximal-distal patterning to explain early specification.
In 3 unrelated individuals with congenital hypogonadotropic hypogonadism (HH20; 615270), Miraoui et al. (2013) identified heterozygosity for missense mutations in the FGF17 gene (603725.0001-603725.0003). One of the 3 probands belonged to a large consanguineous 10-generation French Canadian family with anosmic HH and cleft palate (see HH2, 147950), in which Tornberg et al. (2011) had identified missense mutations in both the FGFR1 (136350.0025) and HS6ST1 (604846.0002) genes; in that proband, Miraoui et al. (2013) also identified 2 missense mutations in another FGF-network gene, FLRT3 (604808.0001 and 604808.0002). Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of congenital HH (CHH) inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
Using whole brain imaging, Cholfin and Rubenstein (2007) found that mice lacking Fgf17 showed a selective reduction in the size of the dorsal frontal cortex, whereas the ventral/orbital frontal cortex was normal. These changes were complemented by a rostromedial shift of sensory cortical areas. The changes in regionalization persisted into adulthood. Cholfin and Rubenstein (2007) concluded that FGF17 functions similarly to FGF8 in patterning the neocortical map, but FGF17 is more selective in regulating the properties of the dorsal but not ventral frontal cortex.
In the female proband from a large consanguineous 10-generation French Canadian family with anosmic hypogonadotropic hypogonadism (HH20; 615270) and cleft palate, previously reported by White et al. (1983) and in whom Tornberg et al. (2011) had identified missense mutations in the FGFR1 (R250Q; 136350.0025) and HS6ST1 (R296W; 604846.0002) genes, Miraoui et al. (2013) also identified heterozygosity for a c.323T-C transition in exon 4 of the FGF17 gene, resulting in an ile108-to-thr (I108T) substitution at a highly conserved residue in the FGF core domain. In addition, the proband was heterozygous and homozygous for 2 missense mutations in another FGF-network gene, FLRT3 (E97G, 604808.0001 and S144I, 604808.0002, respectively). Three other affected family members also carried mutations in the FGFR1, HS6ST1, and FLRT3 genes, and 4 unaffected family members carried 1 or 2 mutations in those genes, but none had a mutation in the FGF17 gene. The I108T mutation was not found in 155 controls or in the 1000 Genomes Project database. Analysis of physical interactions between the ligand-binding region of FGFR1 and FGF17 by surface-plasmon-resonance spectroscopy demonstrated that the I108T mutant was defective in FGFR1 activation compared to wildtype; in addition, the I108T mutant completely failed to activate the R250Q FGFR1 mutant, indicating that these 2 loss-of-function substitutions act in an additive manner.
In a sporadic male patient with congenital hypogonadotropic hypogonadism (HH20; 615270), Miraoui et al. (2013) identified heterozygosity for a c.530G-A transition in exon 5 of the FGF17 gene, resulting in an arg177-to-his (R177H) substitution at a highly conserved residue in the FGF core domain. The patient, who had a normal sense of smell, also displayed low bone mass. The R177H mutation was not found in 155 controls or in the 1000 Genomes Project database. Analysis of physical interactions between the ligand-binding region of FGFR1 (136350) and FGF17 by surface-plasmon-resonance spectroscopy demonstrated that the R177H mutant had dramatically reduced ability to activate FGFR1 compared to wildtype.
In a sporadic male patient with congenital hypogonadotropic hypogonadism (HH20; 615270), who was anosmic, Miraoui et al. (2013) identified heterozygosity for a c.560A-G transition in exon 5 of the FGF17 gene, resulting in an asn187-to-ser (N187S) substitution at a conserved residue in the C terminus. The mutation was not found in 155 controls or in the 1000 Genomes Project database.
Cholfin, J. A., Rubenstein, J. L. R. Patterning of frontal cortex subdivisions by Fgf17. Proc. Nat. Acad. Sci. 104: 7652-7657, 2007. [PubMed: 17442747] [Full Text: https://doi.org/10.1073/pnas.0702225104]
Hoshikawa, M., Ohbayashi, N., Yonamine, A., Konishi, M., Ozaki, K., Fukui, S., Itoh, N. Structure and expression of a novel fibroblast growth factor, FGF-17, preferentially expressed in the embryonic brain. Biochem. Biophys. Res. Commun. 244: 187-191, 1998. [PubMed: 9514906] [Full Text: https://doi.org/10.1006/bbrc.1998.8239]
Krejci, P., Krakow, D., Mekikian, P. B., Wilcox, W. R. Fibroblast growth factors 1, 2, 17, and 19 are the predominant FGF ligands expressed in human fetal growth plate cartilage. Pediat. Res. 61: 267-272, 2007. [PubMed: 17314681] [Full Text: https://doi.org/10.1203/pdr.0b013e318030d157]
Mariani, F. V., Ahn, C. P., Martin, G. R. Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning. Nature 453: 401-405, 2008. [PubMed: 18449196] [Full Text: https://doi.org/10.1038/nature06876]
Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am. J. Hum. Genet. 92: 725-743, 2013. [PubMed: 23643382] [Full Text: https://doi.org/10.1016/j.ajhg.2013.04.008]
Sun, X., Lewandoski, M., Meyers, E. N., Liu, Y.-H., Maxson, R. E., Jr., Martin, G. R. Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development. Nature Genet. 25: 83-86, 2000. [PubMed: 10802662] [Full Text: https://doi.org/10.1038/75644]
Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc. Nat. Acad. Sci. 108: 11524-11529, 2011. [PubMed: 21700882] [Full Text: https://doi.org/10.1073/pnas.1102284108]
White, B. J., Rogol, A. D., Brown, K. S., Lieblich, J. M., Rosen, S. W. The syndrome of anosmia with hypogonadotropic hypogonadism: a genetic study of 18 new families and a review. Am. J. Med. Genet. 15: 417-435, 1983. [PubMed: 6881209] [Full Text: https://doi.org/10.1002/ajmg.1320150307]