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FGFR3
fibroblast growth factor receptor 3
The FGFR3 gene provides instructions for making fibroblast growth factor receptor 3, a protein crucial for regulating cell growth, differentiation, and especially skeletal development. FGFR3 is a gene that encodes a receptor protein vital for various cellular processes, including cell proliferation, differentiation, and tissue development.
FGFR3 is located on the short (p) arm of chromosome 4, at band 4p16.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The FGFR3 gene, also known as fibroblast growth factor receptor 3, is a key component in human development and cellular function. It provides the genetic blueprint for a protein that belongs to a family of four fibroblast growth factor receptors, all sharing similar structural and functional characteristics. These receptors are integral to several fundamental biological processes, such as the regulation of cell growth and division, the determination of cell identity, the formation of new blood vessels (angiogenesis), wound healing, and embryonic development.
A distinctive feature of the FGFR3 protein is its transmembrane structure, meaning one part of the protein is situated inside the cell while another extends beyond the cell's outer surface. This configuration enables the protein to interact with specific growth factors residing outside the cell. Upon binding with these external signals, the FGFR3 protein becomes activated, initiating a sequence of biochemical reactions inside the cell that direct cellular modifications, including the process of maturation into specialised cell types.
What the gene does
The fibroblast growth factor receptor 3 (FGFR3) protein is a crucial transmembrane receptor that mediates extracellular signals to the internal cellular machinery. It is a member of the fibroblast growth factor receptor family, which is involved in a wide array of cellular processes. These include regulating cell proliferation and differentiation, coordinating angiogenesis, facilitating wound healing, and guiding embryonic development.
Specifically, the FGFR3 protein extends through the cell membrane, allowing its external portion to bind with particular growth factors. This binding event activates the receptor, initiating intracellular signalling cascades that influence cell behaviour. Within skeletal tissues, FGFR3 plays a critical role in regulating bone growth by limiting the conversion of cartilage into bone, a process known as ossification. Different versions (isoforms) of the FGFR3 protein are found in various tissues, each interacting with a range of growth factors. Many of these isoforms are highly expressed in bone-forming cells.
One specific isoform of the FGFR3 protein is predominantly located in epithelial cells, such as those forming the outermost layer of the skin, the epidermis, indicating its diverse functional roles across different tissue types.
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Chromosome location
The FGFR3 gene is situated on the short arm of chromosome 4, specifically at position 4p16.3. Its precise genomic location ensures it has a defined place within the human genome, where it can be accurately identified and studied.
Protein structure
The FGFR3 protein is composed of 806 amino acids and exhibits a complex domain architecture essential for its receptor function. The extracellular portion of the protein includes three Ig-like C2-type domains: Ig-like C2-type 1 (spanning amino acids 24-126), Ig-like C2-type 2 (amino acids 151-244), and Ig-like C2-type 3 (amino acids 253-355). These domains are critical for ligand binding. Two Disordered regions (amino acids 126-153 and 765-806) contribute to the protein's flexibility and potential for dynamic interactions. Crucially, the intracellular part of the protein contains a Protein kinase domain (amino acids 472-761), which is responsible for the protein's enzymatic activity, enabling it to phosphorylate target proteins upon activation.
Key variants
Variants within the FGFR3 gene can lead to alterations in the fibroblast growth factor receptor 3 protein, affecting its normal function. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, impacting the protein's ability to regulate cell growth, differentiation, and particularly bone development. The specific location and nature of a variant often determine its effect on protein activity and the resulting clinical outcome. Understanding these variations is essential for comprehending the diverse range of conditions associated with FGFR3.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1031C>G | p.Ser344Cys | Pathogenic/Likely pathogenic | ★★☆☆ | FGFR3-related chondrodysplasia |
c.1043C>G | p.Ser348Cys | Pathogenic/Likely pathogenic | ★★☆☆ | FGFR3-related chondrodysplasia |
c.1052C>G | p.Ser351Cys | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1052C>T | p.Ser351Phe | Pathogenic/Likely pathogenic | ★★☆☆ | Hypochondroplasia |
c.1108G>T | p.Gly370Cys | Pathogenic | ★★☆☆ | Thanatophoric dysplasia type 1 |
c.1111A>T | p.Ser371Cys | Pathogenic | ★★☆☆ | Thanatophoric dysplasia type 1 |
c.1118A>G | p.Tyr373Cys | Pathogenic | ★★☆☆ | Thanatophoric dysplasia type 1 |
c.1138G>A | p.Gly380Arg | Pathogenic | ★★☆☆ | Achondroplasia |
c.1138G>C | p.Gly380Arg | Pathogenic | ★★☆☆ | Achondroplasia |
c.1172C>A | p.Ala391Glu | Pathogenic | ★★☆☆ | Crouzon syndrome-acanthosis nigricans syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the FGFR3 gene are associated with a spectrum of inherited conditions, many of which affect skeletal development. Amongst these, Achondroplasia is the most common form of short-limbed dwarfism. Other related conditions include Hypochondroplasia, which is a milder form of short-limbed dwarfism, and Thanatophoric dysplasia, which can present as Thanatophoric dysplasia type I or Thanatophoric dysplasia type II. The gene also plays a role in certain forms of Craniosynostosis, specifically Muenke craniosynostosis, characterised by premature fusion of skull bones.
- Achondroplasia
- Craniosynostosis (Muenke)
- Hypochondroplasia
- Thanatophoric dysplasia Dedicated page coming soon
- Thanatophoric dysplasia type I Dedicated page coming soon
- Thanatophoric dysplasia type II Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic FGFR3 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The FGFR3 gene is extensively recognised within the UK's genomic healthcare system, as evidenced by its inclusion in numerous NHS Genomic Medicine Service clinical panels. It is evaluated for conditions such as Arthrogryposis, Common craniosynostosis syndromes (R99), Monogenic short stature (R453), and Skeletal dysplasia (R104). The gene is also relevant to Foetal anomalies (R21) and Thanatophoric dysplasia (R25), demonstrating its broad importance in diagnosing a range of developmental and skeletal disorders within the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle can generally support overall well-being, though there is no conclusive evidence that specific lifestyle choices can prevent or cure conditions linked to FGFR3 gene variants. Regular physical activity, a balanced diet rich in fruits, vegetables, and lean proteins, and avoiding smoking and excessive alcohol consumption are widely recommended for general health. Individuals with conditions associated with FGFR3 should discuss any lifestyle modifications with their healthcare provider to ensure they are appropriate and beneficial for their specific circumstances.
Supplement considerations
While certain supplements are marketed for bone health or growth, there is currently no definitive evidence that any specific supplement can prevent, treat, or mitigate the effects of conditions caused by FGFR3 gene variants. For instance, some general population studies suggest that adequate calcium and vitamin D intake supports bone health. However, individuals should consult with a healthcare professional before taking any new supplements, especially if they have a genetic condition, to ensure safety and appropriateness.
Frequently asked questions
What is the primary function of the FGFR3 gene?
The FGFR3 gene provides instructions for creating a protein that acts as a receptor for fibroblast growth factors, playing a crucial role in regulating cell growth, differentiation, and especially the development of bone by controlling the conversion of cartilage to bone.
What conditions are associated with FGFR3 variants?
Variants in the FGFR3 gene are linked to several inherited conditions, predominantly affecting skeletal development. These include Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia (types I and II), and Muenke Craniosynostosis.
How does the FGFR3 protein work?
The FGFR3 protein is a transmembrane receptor. Its external part binds to specific growth factors outside the cell, activating the protein and initiating a series of signals inside the cell that influence various cellular processes, including growth and maturation.
Is FGFR3 included in UK NHS genetic testing panels?
Yes, the FGFR3 gene is part of several NHS Genomic Medicine Service clinical diagnostic panels in the UK. This includes panels for conditions such as Skeletal dysplasia, Monogenic short stature, and Thanatophoric dysplasia.
Can lifestyle changes prevent FGFR3-related conditions?
Currently, there is no conclusive evidence that specific lifestyle choices can prevent or cure conditions caused by FGFR3 gene variants. A generally healthy lifestyle is encouraged for overall well-being, and individuals should consult healthcare professionals for personalised advice.
References
- Robertson AG, Kim J, Al-Ahmadie H. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2018. PMID: 30096301
- Desai SD, Vora R, Bharani S. Garcia-Hafner-Happle syndrome: A case report and review of a rare sub-type of epidermal nevus syndrome. Journal of pediatric neurosciences. 2014. PMID: 24891911
- Chen F, Sarabipour S, Hristova K. Multiple consequences of a single amino acid pathogenic RTK mutation: the A391E mutation in FGFR3. PloS one. 2013. PMID: 23437153
- Chen F, Degnin C, Laederich M. The A391E mutation enhances FGFR3 activation in the absence of ligand. Biochimica et biophysica acta. 2011. PMID: 21536014
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- Arnaud-López L, Fragoso R, Mantilla-Capacho J. Crouzon with acanthosis nigricans. Further delineation of the syndrome. Clinical genetics. 2007. PMID: 17935505
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- Lievens PM, Liboi E. The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. The Journal of biological chemistry. 2003. PMID: 12624096
- Horton WA, Lunstrum GP. Fibroblast growth factor receptor 3 mutations in achondroplasia and related forms of dwarfism. Reviews in endocrine & metabolic disorders. 2002. PMID: 12424440
- van Rhijn BW, van Tilborg AA, Lurkin I. Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders. European journal of human genetics : EJHG. 2002. PMID: 12461689