HGNC Approved Gene Symbol: FGF5
Cytogenetic location: 4q21.21 Genomic coordinates (GRCh38): 4:80,266,588-80,291,017 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q21.21 | Trichomegaly | 190330 | Autosomal recessive | 3 |
Zhan et al. (1988) identified a fifth oncogene related to fibroblast growth factors and termed it FGF5. The other 4 are FGFA (131220), FGFB (134920), INT2 (164950), and HST (164980). FGF5 was discovered when it acquired transforming potential by a DNA rearrangement accompanying transfection of NIH 3T3 cells with human tumor DNA. Two regions of the FGF5 sequence, containing 122 of its 267 amino acid residues, were 40 to 50% homologous to the sequences of the 4 other members of the FGF oncogene family. FGF5 was found to be expressed in neonatal brain and in 3 of 13 human tumor cell lines examined.
Using PCR to amplify fragments of FGF5 and its shorter form, FGF5S, Higgins et al. (2014) observed expression of both forms within human occipital scalp skin and plucked hair fibers. Immunohistochemistry on scalp skin confirmed the presence of FGF5 within the upper outer root sheath cells of human hair follicles as well as in small round perifollicular cells.
The FGF5 gene contains 3 exons (Zhan et al., 1988), a structure typical for members of the FGF oncogene family.
Nguyen et al. (1988) mapped the FGF5 gene to 4q21 by in situ hybridization. Thus, it is not in the same cluster as the related HST and INT2 genes, which are coamplified in some tumor cells and were found by Nguyen et al. (1988), using pulsed field gel analysis, to be separated by only 40 kb. By polymerase chain reaction (PCR) amplification of target sequences in DNAs from somatic cell hybrids, Dionne et al. (1990) mapped the FGF5 gene to chromosome 4. By in situ chromosomal hybridization, Mattei et al. (1992) demonstrated that the corresponding gene in the mouse is on chromosome 5.
C2 cytotoxic T lymphocytes (CTLs), cloned from human CTLs infiltrating a renal cell carcinoma, kill cancer cells overexpressing FGF5. Hanada et al. (2004) showed that C2 cells recognized human leukocyte antigen-A3 MHC class I molecules presenting a 9-residue FGF5 peptide generated by protein splicing. This process, previously described strictly in plants and unicellular organisms, entails posttranslational excision of a polypeptide segment followed by ligation of the newly liberated C- and N-terminal residues. The occurrence of protein splicing in vertebrates has important implications for the complexity of the vertebrate proteome and for the immune recognition of self and foreign peptides.
To assess the effect of FGF5 on the human hair cycle, Higgins et al. (2014) grew microdissected human scalp hair follicles in the presence of recombinant FGF5. The follicles entered catagen prematurely, after 2 to 4 days, in the presence of recombinant FGF5, whereas untreated hairs entered catagen after 5 to 7 days. Growth was significantly reduced after incubation with recombinant FGF5 protein. Higgins et al. (2014) concluded that, whereas a lack of FGF5 results in increased hair length as seen in trichomegaly (TCMGLY; 190330), overexposure to FGF5 inhibits hair growth in an organ culture model by initiating catagen.
In affected individuals from 3 unrelated Pakistani families with trichomegaly (190330), Higgins et al. (2014) identified homozygosity for mutations in the FGF5 gene (165190.0001-165190.0003, respectively). The mutations, which segregated with disease in each family, were not found in 50 ethnically matched controls or in public databases. Immunofluorescence studies showed complete absence of FGF5 in plucked forearm hair fibers from affected individuals. Higgins et al. (2014) concluded that FGF5 is a crucial regulator of hair growth.
Hebert et al. (1994) found that mice homozygous for a null allele of the Fgf5 gene, produced by gene targeting in embryonic stem cells, have abnormally long hair. This phenotype appeared identical to that of mice homozygous for the spontaneous mutation 'angora' (go). The transgenic mutant and the 'go' mutant failed to complement one another, and exon 1 of Fgf5 was found to be deleted in DNA from go homozygotes. Expression of Fgf5 is detected in hair follicles from wildtype mice and is localized to the outer root sheath during the anagen VI phase of the hair growth cycle. The findings were interpreted as evidence that FGF5 functions as an inhibitor of hair elongation, thus identifying a molecule whose normal function is apparently to regulate one step in the progression of the follicle through the hair growth cycle. It will be of interest to search for mutations in the FGF5 gene in hypertrichosis universalis (145700, 145701) as well as in other forms of hypertrichosis such as hairy elbows (139600).
Cadieu et al. (2009) performed genomewide association studies of more than 1,000 dogs from more than 80 domestic breeds to identify genes associated with canine fur phenotypes (coat growth pattern, length, and curl). Taking advantage of both inter- and intrabreed variability, they identified distinct mutations in 3 genes, RSPO2 (610575), FGF5, and KRT71 (608245), that together account for most coat phenotypes in purebred dogs in the United States. The combination of mutations in these 3 genes account for 7 different types of coat phenotype in the dog. Thus, Cadieu et al. (2009) concluded that an array of varied and seemingly complex phenotypes can be reduced to the combinatorial effects of only a few genes. A SNP in the FGF5 gene is associated with hair length in dogs.
In affected members of a large consanguineous Pakistani family with trichomegaly (TCMGLY; 190330), Higgins et al. (2014) identified homozygosity for a 1-bp deletion at the donor splice site of intron 2 (c.459+1delG) of the FGF5 gene. The mutation, which segregated with disease in the family, was not found in 50 ethnically matched controls or in public databases. Whole-mount immunofluorescence studies of plucked forearm hair fibers demonstrated complete absence of FGF5 and very low levels of FGF5S in patient hair compared to controls.
In affected members of a large consanguineous Pakistani family with trichomegaly (TCMGLY; 190330), Higgins et al. (2014) identified homozygosity for a 2-bp deletion (c.159_160delTA) in exon 1 of the FGF5 gene, predicted to cause a frameshift affecting both FGF5 and its shorter form, FGF5S. The mutation, which segregated with disease in the family, was not found in 50 ethnically matched controls or in public databases. Whole-mount immunofluorescence studies of plucked forearm hair fibers demonstrated complete absence of FGF5 or FGF5S in patient hair compared to controls.
In a Pakistani patient with trichomegaly (TCMGLY; 190330), Higgins et al. (2014) identified homozygosity for a c.520T-C transition in exon 3 of the FGF5 gene, resulting in a tyr174-to-his (Y174H) substitution at a highly conserved residue within a hydrophobic core. The mutation, which segregated with disease in the family, was not found in 50 ethnically matched controls or in public databases.
Cadieu, E., Neff, M. W., Quignon, P., Walsh, K., Chase, K., Parker, H. G., VonHoldt, B. M., Rhue, A., Boyko, A., Byers, A., Wong, A., Mosher, D. S., Elkahloun, A. G., Spady, T. C., Andre, C., Lark, K. G., Cargill, M., Bustamante, C. D., Wayne, R. K., Ostrander, E. A. Coat variation in the domestic dog is governed by variants in three genes. Science 326: 150-153, 2009. [PubMed: 19713490] [Full Text: https://doi.org/10.1126/science.1177808]
Dionne, C. A., Kaplan, R., Seuanez, H., O'Brien, S. J., Jaye, M. Chromosome assignment by polymerase chain reaction techniques: assignment of the oncogene FGF-5 to human chromosome 4. Biotechniques 8: 190-194, 1990. [PubMed: 2317376]
Hanada, K., Yewdell, J. W., Yang, J. C. Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature 427: 252-256, 2004. [PubMed: 14724640] [Full Text: https://doi.org/10.1038/nature02240]
Hebert, J. M., Rosenquist, T., Gotz, J., Martin, G. R. FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations. Cell 78: 1017-1025, 1994. [PubMed: 7923352] [Full Text: https://doi.org/10.1016/0092-8674(94)90276-3]
Higgins, C. A., Petukhova, L., Harel, S., Ho, Y. Y., Drill, E., Shapiro, L., Wajid, M., Christiano, A. M. FGF5 is a crucial regulator of hair length in humans. Proc. Nat. Acad. Sci. 111: 10648-10653, 2014. [PubMed: 24989505] [Full Text: https://doi.org/10.1073/pnas.1402862111]
Mattei, M.-G., Pebusque, M.-J., Birnbaum, D. Chromosomal localizations of mouse Fgf2 and Fgf5 genes. Mammalian Genome 2: 135-137, 1992. [PubMed: 1543906] [Full Text: https://doi.org/10.1007/BF00353862]
Nguyen, C., Roux, D., Mattei, M.-G., de Lapeyriere, O., Goldfarb, M., Birnbaum, D., Jordan, B. R. The FGF-related oncogenes hst and int.2, and the bcl.1 locus are contained within one megabase in band q13 of chromosome 11, while the fgf.5 oncogene maps to 4q21. Oncogene 3: 703-708, 1988. [PubMed: 2577873]
Zhan, X., Bates, B., Hu, X., Goldfarb, M. The human FGF-5 oncogene encodes a novel protein related to fibroblast growth factors. Molec. Cell. Biol. 8: 3487-3495, 1988. [PubMed: 3211147] [Full Text: https://doi.org/10.1128/mcb.8.8.3487-3495.1988]