Fibroblast growth factor receptor 3
Gene involved in the most common form of dwarfism
Fibroblast growth factor receptor 3 (FGFR-3) is a protein that in humans is encoded by the FGFR3 gene. FGFR3 has also been designated as CD333 (cluster of differentiation 333). The gene, which is located on chromosome 4, location p16.3, is expressed in tissues such as the cartilage, brain, intestine, and kidneys.
The FGFR3 gene produces various forms of the FGFR-3 protein; the location varies depending on the isoform of FGFR-3. Since the different forms are found within different tissues the protein is responsible for multiple growth factor interactions. Gain of function mutations in FGFR3 inhibits chondrocyte proliferation and underlies achondroplasia and hypochondroplasia.
01Function
FGFR-3 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 FGFR-3 protein plays a role in bone growth by regulating ossification. 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.
02Mutations
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" 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. 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.
FGFR3 mutations are also linked with spermatocytic tumor, which occur more frequently in older men.
03Disease linkage
Defects in the FGFR3 gene has been associated with several conditions, including craniosynostosis and seborrheic keratosis.
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.
Post-translational modification of FGFR3 occur in bladder cancer that do not occur in normal cells and can be targeted by immunotherapeutic antibodies.
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. 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. Only a single copy of the mutated FGFR3 gene results in achondroplasia. 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.
Thanatophoric dysplasia
Thanatophoric dysplasia is a genetic disorder caused by mutations in FGFR3 that is often fatal. There are two types. TD type I is caused by a premature stop codon mutation. TD type II is a result of the Lys650Glu missense mutation which is located in the tyrosine kinase region of FGFR3.
Muenke syndrome
Muenke syndrome, a disorder characterized by craniosynostosis, is caused by protein changes on FGFR3. The specific pathogenic variant c.749C>G changes the protein p.Pro250Arg, in turn resulting in this condition. Characteristics of Muenke syndrome include coronal synostosis (usually bilateral), midfacial retrusion, strabismus, hearing loss, and developmental delay. Turribrachycephaly, cloverleaf skull, and frontal bossing are also possible.
04As a drug target
An FGFR3 inhibitor known as erdafitinib has been approved as a cancer treatment in several jurisdictions for FGFR3+ urothelial carcinoma.
Additional FGFR3 inhibitors that have reached clinical testing include:
| Drug | Disease / clinical setting | Qualifying FGFR3 alteration | Highest relevant clinical stage |
|---|---|---|---|
| Erdafitinib | Locally advanced or metastatic urothelial carcinoma | Susceptible activating FGFR3 mutations; FGFR2/3 rearrangements or fusions | Phase III; approved |
| " | Non-muscle-invasive bladder cancer | Activating FGFR3 mutation or FGFR3 fusion/rearrangement | Phase II |
| " | Recurrent diffuse glioma / glioblastoma | FGFR3-TACC3 fusion and other eligible FGFR-TACC fusions | Phase II |
| " | Advanced solid tumours, tumour-agnostic basket setting | Activating FGFR3 mutation or FGFR3 fusion/rearrangement | Phase II |
| Infigratinib | Achondroplasia | Germline activating FGFR3 variants, predominantly p.Gly380Arg | Phase II |
| " | Hypochondroplasia | Germline activating FGFR3 variants, commonly p.Asn540Lys | Phase II/III |
| " | Muscle-invasive urothelial carcinoma, adjuvant setting | FGFR3 alteration | Phase III |
| Fexagratinib | Recurrent high-grade diffuse glioma / glioblastoma | FGFR3-TACC3 fusion or eligible FGFR fusion | Phase I/II |
| Vepugratinib | Untreated unresectable locally advanced or metastatic urothelial carcinoma | A qualifying FGFR3 genetic alteration, including mutation or fusion | Phase III |
| Dabogratinib | Achondroplasia | Germline activating FGFR3 variant; BEACH301 enrols children with molecularly confirmed p.Gly380Arg | Phase II |
| " | Low-grade, intermediate-risk non-muscle-invasive bladder cancer | FGFR3-altered tumour | Phase II |
| " | Low-grade upper-tract urothelial carcinoma | Predominantly FGFR3-driven tumours; patient-specific trial eligibility should be verified from the protocol | Phase IIa/b |
| " | Advanced/metastatic urothelial cancer and other FGFR3-altered solid tumours | Activating FGFR3 mutation or fusion/rearrangement, including resistance-associated gatekeeper mutations | Phase I/II |
05Interactions
Sources and credits
This article is adapted from the Wikipedia article “Fibroblast growth factor receptor 3”, written by its contributors and licensed under CC BY-SA 4.0. Fathomly has changed the layout, removed citation markers, navigation and maintenance notices, and adjusted punctuation. This adapted version is shared under the same license. For references, see the original article.
Images, from Wikimedia Commons:
- Ideogram human chromosome 4.svg by National Center for Biotechnology Information, U.S. National Library of Medicine, Public domain
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