FGFR3 gene

Last updated on: 26.10.2021

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Definition
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The FGFR3 gene (FGFR is the acronym for fibroblast growth factor receptor) belongs to the FGFR gene family, which includes the 4 members FGFR1-4, which have a high sequence homology of 55-72%. FGFR3, also known as CD333, is located on chromosome 4, position p16.3. It is expressed in tissues such as cartilage, brain, intestine and kidney (Wang Y et al. 2013).

Alternative splicing of FGFR1-3 transcripts results in the formation of multiple isoforms, some with widely varying ligand binding specificity. The natural ligands of FGFR are the FGFs. In total, the FGF family comprises 22 known family members (FGF1-14 and FGF16-23).

General information
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The FGFR3 gene encodes different forms of FGFR3 proteins. The different recptor proteins are expressed in different tissues. They are members of the fibroblast growth factor receptor family. Their amino acid sequence is evolutionarily highly conserved.

FGFR family members differ from each other in their ligand affinities and tissue distribution. Gain-of-function mutations in FGFR3 inhibit chondrocyte proliferation and underlie achondroplasia and hypochondroplasia.

Function: The FGF receptor protein consists 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 and initiates a cascade of downstream signals that ultimately influence cell proliferation and differentiation. FGFR- protein binds to both acidic and basic fibroblast growth factor and plays a role in bone development and maintenance. Thus, the FGFR3 protein regulates the ossification process during bone growth.

Clinical picture
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Mutations. Gain-of-function mutations in the coding gene can develop dysfunctional proteins "that impede cartilage growth and development and impair chondrocyte proliferation and calcification". Mutaions can lead to craniosynostosis and various 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 (Foldynova-Trantirkova S et al. 2013). This point mutation in the FGFR3 gene causes hydrogen bonds to form between two arginine side chains, resulting in ligand-independent stabilization of FGFR3 dimers. Overactivity of FGFR3 inhibits chondrocyte proliferation and limits long bone length.

FGFR3 mutations are also associated with spermatocyte tumors, which are more common in older men (Kelleher FC et al. 2013).

Defects in the FGFR3 gene have been associated with several diseases, including craniosynostosis and in epidermal nevi as well as seborrheic keratoses (Hafner C et al (2007).

Urinary bladder carcinoma: Mutations of FGFR3, FGFR3-TACC3 and FGFR3-BAIAP2L1 fusion proteins are frequently associated with bladder carcinoma, with some FGFR3 mutations also associated with better prognosis. Therefore, FGFR3 represents a potential therapeutic target for the treatment of bladder cancer (di Martino E et al 2016). In bladder carcinoma, post-translational modifications of FGFR3 occur that are physiologically absent and can be targeted by immunotherapeutic antibodies.

Glioblastoma: FGFR3-TACC3 fusions have been identified as a primary mitogenic driver in a subset of glioblastomas (approximately 4%) and other gliomas and may be associated with slightly improved overall survival (Mata, Douglas A et al 2020). FGFR3-TACC3 fusion represents a potential therapeutic target in glioblastoma.

Achondroplasia: Achondroplasia is a dominant genetic disorder caused by mutations in FGFR3 that render the resulting protein overactive. Individuals with this mutation have a head circumference that is larger than normal and are significantly smaller in height. Only a single copy of the mutated FGFR3 gene causes achondroplasia. It is generally caused by spontaneous mutations in germ cells; in about 80 percent of cases, parents with children who have this disorder are normal in height.

Thanatophoric dysplasia: Thanatophoric dysplasia is a genetic disorder caused by gain-of-function mutations in FGFR3 and is often fatal in the perinatal period. There are two types. TD type I is caused by a stop codon mutation located in a portion of the gene that encodes the extracellular domain of the protein. TD type II is caused by a substitution in an Lsy650Glu located in the tyrosine kinase domain of FGFR3 (Karczeski B et al. 1993).

Therapy
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FGFR3 inhibitors are in early clinical trials as cancer therapies, e.g. BGJ398 for urothelial carcinoma (Pal SK et al. (2018). The FGFR3 receptor has a tyrosine kinase signaling pathway associated with many biological developments in embryo and tissue. The study of tyrosine kinase signaling pathway exhibited by FGFR3 has played a crucial role in the study of various cellular activities such as cell proliferation and cellular resistance to anticancer drugs.

Literature
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  1. di Martino E et al (2016) A place for precision medicine in bladder cancer: targeting the FGFRs. Future Oncology (London, England) 12: 2243-63
  2. Foldynova-Trantirkova S et al (2013) Sixteen years and counting: the current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Human Mutation 33: 29-41.
  3. Hafner C et al. (2007) FGFR3 mutations in epidermal nevi and seborrheic keratoses: lessons from urothelium and skin. The Journal of Investigative Dermatology 127: 1572-1573.
  4. Karczeski B et al (1993) Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds). Thanatophoric dysplasia. GeneReviews. University of Washington, Seattle. PMID 20301540.
  5. Kelleher FC et al. (2013) Fibroblast growth factor receptors, developmental corruption and malignant disease. Carcinogenesis 34: 2198-2205.
  6. Mata, Douglas A et al (2020) Genetic and epigenetic landscape of IDH-wildtype glioblastomas with FGFR3-TACC3 fusions. Acta Neuropathologica Communications. 8: 186.
  7. Pal SK et al (2018) FGFR3 Alterations. Cancer Discovery 8: 812-821
  8. Wang Y et al (2013) Advances in research on and diagnosis and treatment of achondroplasia in China. Intractable & Rare Diseases Research 2: 45-50.

Incoming links (3)

CD333; Driver mutation; FGFR3-gene;

Last updated on: 26.10.2021