Biology:Fibroblast growth factor receptor 3

Short description: Gene involved in the most common form of dwarfism

 Generic protein structure example

Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene.[1] FGFR3 has also been designated as CD333 (cluster of differentiation 333). The gene, which is located on chromosome 4, location q16.3, is expressed in tissues such as the cartilage, brain, intestine, and kidneys.[2]

The FGFR3 gene produces various forms of the FGFR3 protein; the location varies depending on the isoform of the FGFR3 protein. Since the different forms are found within different tissues the protein is responsible for multiple growth factor interactions.[3] Gain of function mutations in FGFR3 inhibits chondrocyte proliferation and underlies achondroplasia and hypochondroplasia.

Function

The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals which ultimately influence cell mitogenesis and differentiation.

This particular family member binds both acidic and basic fibroblast growth factor and plays a role in bone development and maintenance. The FGFR3 protein plays a role in bone growth by regulating ossification.[3] Alternative splicing occurs and additional variants have been described, including those utilizing alternate exon 8 rather than 9, but their full-length nature has not been determined.[4]

Mutations

Simplification on the mutation 46 XX 4q16.3 (female), 46XY 4q16.3 (male). Gain of function mutations in this gene can develop dysfunctional proteins "impede cartilage growth and development and affect chondrocyte proliferation and calcification"[2] which can lead to craniosynostosis and multiple types of skeletal dysplasia (osteochondrodysplasia).

In achondroplasia, the FGFR3 gene has a missense mutation at nucleotide 1138 resulting from either a G>A or G>C.[5] This point mutation in the FGFR3 gene causes hydrogen bonds to form between two arginine side chains leading to ligand-independent stabilization of FGFR3 dimers. Overactivity of FGFR3 inhibits chondrocyte proliferation and restricts long bone length.[3]

FGFR3 mutations are also linked with spermatocytic tumor, which occur more frequently in older men.[6]

Disease linkage

Defects in the FGFR3 gene has been associated with several conditions, including craniosynostosis and seborrheic keratosis.[7]

Bladder cancer

Mutations of FGFR3, FGFR3–TACC3 and FGFR3–BAIAP2L1 fusion proteins are frequently associated with bladder cancer, while some FGFR3 mutations are also associated with a better prognosis. Hence FGFR3 represents a potential therapeutic target for the treatment of bladder cancer.[8]

Post-translational modification of FGFR3 occur in bladder cancer that do not occur in normal cells and can be targeted by immunotherapeutic antibodies.[9]

Glioblastoma

FGFR3-TACC3 fusions have been identified as the primary mitogenic drivers in a subset of glioblastomas (approximately 4%) and other gliomas and may be associated with slightly improved overall survival.[10] The FGFR3-TACC3 fusion represents a possible therapeutic target in glioblastoma.

Achondroplasia

Achondroplasia is a dominant genetic disorder caused by mutations in FGFR3 that make the resulting protein overactive. Individuals with these mutation have a head size that is larger than normal and are significantly shorter in height.[11][12] Only a single copy of the mutated FGFR3 gene results in achondroplasia.[13] It is generally caused by spontaneous mutations in germ cells; roughly 80 percent of the time, parents with children that have this disorder are normal size.[12][13]

Thanatophoric dysplasia

Thanatophoric dysplasia is a genetic disorder caused by gain-of-function mutations in FGFR3 that is often fatal during the perinatal period because the child cannot breathe.[14][15] There are two types. TD type I is caused by a stop codon mutation that is located in part of the gene coding for the extracellular domain of the protein.[14] TD type II is a result of a substitution in a Lsy650Glu which is located in the tyrosine kinase area of FGFR3.[14]

As a drug target

FGFR3 inhibitors are in early clinical trials as a cancer treatment, eg. BGJ398 for urothelial carcinoma.Cite error: Closing </ref> missing for <ref> tag[16] and FGF9.[17][16]

References

1. "Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3". Proceedings of the National Academy of Sciences of the United States of America 88 (4): 1095–9. February 1991. doi:10.1073/pnas.88.4.1095. PMID 1847508. Bibcode1991PNAS...88.1095K.
2. "Advances in research on and diagnosis and treatment of achondroplasia in China". Intractable & Rare Diseases Research 2 (2): 45–50. May 2013. doi:10.5582/irdr.2013.v2.2.45. PMID 25343101.
3. "FGFR3 gene". Genetics Home Reference. U.S. National Library of Medicine.
4. "Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias". Human Mutation 33 (1): 29–41. January 2012. doi:10.1002/humu.21636. PMID 22045636.
5. "Fibroblast growth factor receptors, developmental corruption and malignant disease". Carcinogenesis 34 (10): 2198–205. October 2013. doi:10.1093/carcin/bgt254. PMID 23880303.
6. "FGFR3 mutations in epidermal nevi and seborrheic keratoses: lessons from urothelium and skin". The Journal of Investigative Dermatology 127 (7): 1572–3. July 2007. doi:10.1038/sj.jid.5700772. PMID 17568799.
7. "A place for precision medicine in bladder cancer: targeting the FGFRs". Future Oncology (London, England) 12 (19): 2243–63. October 2016. doi:10.2217/fon-2016-0042. PMID 27381494.
8. "Post-translational modifications in bladder cancer: Expanding the tumor target repertoire". Urologic Oncology 38 (12): 858–866. October 2018. doi:10.1016/j.urolonc.2018.09.001. PMID 30342880.
9. Mata, Douglas A.; Benhamida, Jamal K.; Lin, Andrew L.; Vanderbilt, Chad M.; Yang, Soo-Ryum; Villafania, Liliana B.; Ferguson, Donna C.; Jonsson, Philip et al. (2020). "Genetic and epigenetic landscape of IDH-wildtype glioblastomas with FGFR3-TACC3 fusions". Acta Neuropathologica Communications 8 (1): 186. doi:10.1186/s40478-020-01058-6. PMID 33168106.
10. "Achondroplasia". Genetic and Rare Diseases Information Center (GARD).
11. "FGFR3 gene". Genetics Home Reference. U.S. National Library of Medicine.
12. "Learning about Achondroplasia". National Human Genome Research Institute.
13. Thanatophoric Dysplasia. University of Washington, Seattle. 1993. Retrieved 2018-11-17.
14. "Thanatophoric dwarfism. Two case reports and survey of the literature". Clinical Pediatrics 16 (8): 690–7. August 1977. doi:10.1177/000992287701600803. PMID 872478.
15. "Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity". The Journal of Biological Chemistry 274 (49): 34785–94. December 1999. doi:10.1074/jbc.274.49.34785. PMID 10574949.
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