Alternative titles; symbols
HGNC Approved Gene Symbol: FGF9
Cytogenetic location: 13q12.11 Genomic coordinates (GRCh38): 13:21,671,073-21,704,498 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q12.11 | Multiple synostoses syndrome 3 | 612961 | Autosomal dominant | 3 |
Members of the fibroblast growth factor (FGF) gene family, such as FGF9, are peptide regulatory factors that act through distinct tyrosine kinase receptors and are involved in various biologic processes during embryogenesis and adult life, including implantation, morphogenesis, angiogenesis, and possibly tumorigenesis (Miyamoto et al., 1993; Mattei et al., 1995).
Miyamoto et al. (1993) purified a 30-kD heparin-binding polypeptide in the culture supernatant of a human glioma cell line. By PCR of the isolated N-terminal sequence, followed by screening a human foreskin cDNA library, Miyamoto et al. (1993) cloned FGF9. The deduced 208-amino acid protein shares 94% sequence homology with rat Fgf9. Northern blot analysis in human glioma cells detected a major 4.3-kb band and minor 3.4- and 2.7-kb bands. Northern blot analysis of rat tissues detected strong expression in kidney and low expression in brain.
Wu et al. (2009) stated that the FGF9 gene contains 3 exons.
By radioactive chromosomal in situ hybridization, Mattei et al. (1995) mapped the FGF9 gene to chromosome 13q11-q12.
By genomic sequence analysis, Katoh and Katoh (2005) mapped the FGF9 gene to chromosome 13q12.11 in a head-to-head orientation with the EFHA1 gene (610632). They determined that the FGF9-EFHA1 locus and the FGF20 (605558)-EFHA2 (610633) locus on chromosome 8p22 are paralogous regions within the human genome.
Using the Cre/loxP system, Sun et al. (2000) found that maintenance of Fgf9 and Fgf17 (603725) expression is dependent on Shh (600725), whereas Fgf8 (600483) 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.
Mariani et al. (2008) demonstrated that mouse limbs lacking Fgf4 (164980), Fgf9, and Fgf17 have normal skeletal pattern, indicating that Fgf8 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.
Bowles et al. (2010) noted that retinoic acid (RA) upregulates Stra8 (609987) expression and triggers ovarian germ cells to enter meiosis. Using mouse cultured gonads, they showed that Fgf9 was produced in developing testis and inhibited germ cell meiosis by making them less responsive to RA. In vivo analysis in mice revealed that Fgf9 acted directly on germ cells, not via somatic cells of fetal testis, to impede Stra8 upregulation by RA. The authors concluded that RA and FGF9 determine germ cell sexual fate through their antagonist actions, with RA pushing germ cells toward oogenesis and FGF9 pushing them toward a male fate.
In a 5-generation Chinese family with autosomal dominant multiple synostoses syndrome mapping to chromosome 13q11-q12 (SYNS3; 612961), Wu et al. (2009) identified a heterozygous missense mutation in the FGF9 gene (S99N; 600921.0001) that segregated with disease and was not found in 250 unrelated ethnically matched controls.
In a Spanish father and son with multiple synostoses syndrome, including sagittal suture synostosis, Rodriguez-Zabala et al. (2017) identified heterozygosity for a missense mutation in the FGF9 gene (R62G; 600921.0002) that segregated with disease in the family and was not found in 150 Spanish controls or in the gnomAD database.
By combining a chromosome-scale genome assembly of the Iberian mole, Talpa occidentalis, with transcriptomic, epigenetic, and chromatin interaction datasets, Real et al. (2020) identified rearrangements that altered the regulatory landscape of genes with distinct gonadal expression patterns. These included a tandem triplication involving Cyp17a1 (609300), a gene controlling androgen synthesis, and an intrachromosomal inversion involving Fgf9, a protesticular growth factor gene that is heterochronically expressed in mole ovotestes. Transgenic mice with a knockin mole Cyp17a1 enhancer or overexpressing Fgf9 showed phenotypes recapitulating mole sexual features, including development of masculinizing ovotestes in females.
Colvin et al. (2001) reported male-to-female sex reversal in mice lacking Fgf9, demonstrating a novel role for FGF signaling in testicular embryogenesis. Fgf9 -/- mice also exhibited lung hypoplasia and died at birth. Reproductive system phenotypes ranged from testicular hypoplasia to complete sex reversal, with most Fgf9 -/- XY reproductive systems appearing grossly female at birth. Fgf9 appeared to act downstream of Sry (480000) to stimulate mesenchymal proliferation, mesonephric cell migration, and Sertoli cell differentiation in the embryonic testis. While Sry is found only in some mammals, Fgfs are highly conserved. Thus, Fgfs may function in sex determination and reproductive system development in many species.
The dominant mouse mutant 'elbow knee synostosis' (Eks) is characterized by radiohumeral and tibiofemoral synostosis, craniosynostosis, and lung hypoplasia. Harada et al. (2009) identified a mutation in the Fgf9 gene that resulted in an asn143-to-thr substitution in Eks mice. The Fgf9(Eks) mutation prevented homodimerization of Fgf9, consequently decreasing the affinity of Fgf9 for heparin. As a result, Fgf9(Eks) was more diffusible in developing tissues, leading to ectopic Fgf9 signaling in prospective joints and sutures, where it repressed development. The reduction in Fgf9 affinity for heparin appeared to be due to the predominance of the monomeric form rather than to changes in its intrinsic affinity for heparin. Harada et al. (2009) concluded that the affinity of FGF9 for heparin sulfate proteoglycan, and therefore the range of FGF9 signaling in developing tissue, is controlled, at least in part, by FGF9 monomer-dimer equilibrium.
In the developing mouse kidney, Barak et al. (2012) demonstrated that Fgf9 and Fgf20 (605558) act as ligands for the niche signal required to maintain stem cells in the progenitor state. Studies of mutant mice with various combinations of loss of Fgf20 and Fgf9 showed that these 2 genes acted redundantly and were essential for kidney development. Reduction of Fgf20 and Fgf9 levels resulted in a reduction in kidney size and fewer glomeruli resulting from a smaller progenitor pool that differentiated normally. One wildtype Fgf20 allele in Fgf9-null embryos was enough to support normal kidney development, but Fgf20-null embryos with 1 wildtype Fgf9 allele had a more severe phenotype, suggesting that Fgf20 has a more dominant role than Fgf9 in the kidney. Fgf20-null kidneys with 1 wildtype Fgf9 allele were characterized by a loss of progenitor cells and the presence of premature differentiation of functional nephrons. Fgf20 was expressed exclusively within nephron progenitors, whereas Fgf9 was expressed mostly in the ureteric bud with signaling to the metanephric mesenchyme. In vitro studies indicated that Fgf20 or Fgf9, alone or together with Bmp7 (112267), maintained isolated metanephric mesenchyme and nephron progenitors that remained competent to differentiate.
Tang et al. (2017) found that both heterozygous and homozygous knockin mice with the S99N mutation (600921.0001) displayed a SYNS3 (612961)-like phenotype, with curly tails and partially or fully fused multiple joints. Observation of joint morphology at different stages of limb development revealed that joint synostosis in homozygous Fgf9 S99N knockin mice was caused by failure of interzone formation with excess chondrogenesis. Fgf9 inhibited mesenchymal cell differentiation into chondrocytes through downregulation of Sox6 (607257) and Sox9 (608160) in wildtype mice, but the S99N mutation attenuated the inhibitory effect in mutant mice. Fgf9 also maintained Gdf5 (601146) expression in elbow and knee joints during development of wildtype mice, but the S99N mutation abolished Gdf5 expression in the prospective elbow and knee joint regions. In addition, the S99N mutation lowered the affinity of Fgf9 to its receptors by changing its conformation, leading to reduced Fgf9 signaling in the presumed joint regions of limbs.
In 12 affected members of a 5-generation Chinese family with autosomal dominant multiple synostoses syndrome (SYNS3; 612961), Wu et al. (2009) identified heterozygosity for a 296G-A transition in exon 2 of the FGF9 gene, resulting in a ser99-to-asn (S99N) substitution predicted to alter binding to FGFR3 (134934). The mutation was not found in unaffected family members or in 250 unrelated ethnically matched controls. In vitro studies demonstrated that mutant FGF9 was expressed and secreted as efficiently as wildtype in transfected cells; however, it induced compromised chondrocyte proliferation and differentiation, accompanied by enhanced osteogenic differentiation and matrix mineralization of bone marrow-derived mesenchymal stem cells. Biochemical analysis revealed that the S99N mutation caused significantly impaired FGF signaling, as evidenced by diminished activity of the ERK1/2 pathway (see 176948) and decreased beta-catenin (116806) and c-MYC (190080) expression when compared with wildtype FGF9. Binding of mutant protein to the receptor FGFR3 was severely impaired, although homodimerization of mutant FGF9 to itself or wildtype was not detectably affected, providing a basis for the observed defective FGF9 signaling.
In a Spanish father and son with multiple synostoses syndrome (SYNS3; 612961), including sagittal suture synostosis, Rodriguez-Zabala et al. (2017) identified heterozygosity for a c.184A-G transition (c.184A-G, NM002010.2) in exon 1 of the FGF9 gene, resulting in an arg62-to-gly (R62G) substitution at a highly conserved residue. The mutation segregated with disease in the family and was not found in 150 Spanish controls or the gnomAD database. The variant appeared to have arisen de novo in the father, as it was not detected in the biologically confirmed unaffected paternal grandparents. In situ proximity ligation assays demonstrated reduced homodimerization with the R62G mutant (68%) compared to wildtype FGF9. In addition, mutant FGF9 showed impaired binding to the high-affinity receptor FGFR3 (134934), causing significantly impaired FGF signaling as evidenced by diminished activity of the Ras-MAPK (see 176948) pathway.
Barak, H., Huh, S.-H., Chen, S., Jeanpierre, C., Martinovic, J., Parisot, M., Bole-Feysot, C., Nitschke, P., Salomon, R., Antignac, C., Ornitz, D. M., Kopan, R. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev. Cell 22: 1191-1207, 2012. [PubMed: 22698282] [Full Text: https://doi.org/10.1016/j.devcel.2012.04.018]
Bowles, J., Feng, C.-W., Spiller, C., Davidson, T.-L., Jackson, A., Koopman, P. FGF9 suppresses meiosis and promotes male germ cell fate in mice. Dev. Cell 19: 440-449, 2010. [PubMed: 20833365] [Full Text: https://doi.org/10.1016/j.devcel.2010.08.010]
Colvin, J. S., Green, R. P., Schmahl, J., Capel, B., Ornitz, D. M. Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104: 875-889, 2001. [PubMed: 11290325] [Full Text: https://doi.org/10.1016/s0092-8674(01)00284-7]
Harada, M., Murakami, H., Okawa, A., Okimoto, N., Hiraoka, S., Nakahara, T., Akasaka, R., Shiraishi, Y., Futatsugi, N., Mizutani-Koseki, Y., Kuroiwa, A., Shirouzu, M., Yokoyama, S., Taiji, M., Iseki, S., Ornitz, D. M., Koseki, H. FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion. Nature Genet. 41: 289-298, 2009. [PubMed: 19219044] [Full Text: https://doi.org/10.1038/ng.316]
Katoh, M., Katoh, M. Comparative genomics on FGF20 orthologs. Oncol. Rep. 14: 287-290, 2005. [PubMed: 15944804]
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]
Mattei, M.-G., Penault-Llorca, F., Coulier, F., Birnbaum, D. The human FGF9 gene maps to chromosomal region 13q11-q12. Genomics 29: 811-812, 1995. [PubMed: 8575785] [Full Text: https://doi.org/10.1006/geno.1995.9926]
Miyamoto, M., Naruo, K.-I., Seko, C., Matsumoto, S., Kondo, T., Kurokawa, T. Molecular cloning of a novel cytokine cDNA encoding the ninth member of the fibroblast growth factor family, which has a unique secretion property. Molec. Cell. Biol. 13: 4251-4259, 1993. [PubMed: 8321227] [Full Text: https://doi.org/10.1128/mcb.13.7.4251-4259.1993]
Real, F. M., Haas, S. A., Franchini, P., Xiong, P., Simakov, O., Kuhl, H., Schopflin, R., Heller, D., Moeinzadeh, M-H., Heinrich, V., Krannich, T., Bressin, A., and 17 others. The mole genome reveals regulatory rearrangements associated with adaptive intersexuality. Science 370: 208-214, 2020. [PubMed: 33033216] [Full Text: https://doi.org/10.1126/science.aaz2582]
Rodriguez-Zabala, M., Aza-Carmona, M., Rivera-Pedroza, C. I., Belinchon, A., Guerrero-Zapata, I., Barraza-Garcia, J., Vallespin, E., Lu, M., del Pozo, A., Glucksman, M. J., Santos-Simarro, F., Heath, K. E. FGF9 mutation causes craniosynostosis along with multiple synostoses. Hum. Mutat. 38: 1471-1476, 2017. [PubMed: 28730625] [Full Text: https://doi.org/10.1002/humu.23292]
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]
Tang, L., Wu, X., Zhang, H., Lu, S., Wu, M., Shen, C., Chen, X., Wang, Y., Wang, W., Shen, Y., Gu, M., Ding, X., Jin, X., Fei, J., Wang, Z. A point mutation in Fgf9 impedes joint interzone formation leading to multiple synostoses syndrome. Hum. Molec. Genet. 26: 1280-1293, 2017. [PubMed: 28169396] [Full Text: https://doi.org/10.1093/hmg/ddx029]
Wu, X., Gu, M., Huang, L., Liu, X., Zhang, H., Ding, X., Xu, J., Cui, B., Wang, L., Lu, S, Chen, X., Zhang, H., Huang, W., Yuan, W., Yang, J., Gu, Q., Fei, J., Chen, Z., Yuan, Z., Wang, Z. Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene. Am. J. Hum. Genet. 85: 53-63, 2009. [PubMed: 19589401] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.007]