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FGFR1
fibroblast growth factor receptor 1
The *FGFR1* gene provides instructions for the fibroblast growth factor receptor 1 protein, which is integral to cellular signalling pathways governing cell growth, development, and differentiation across multiple organ systems. The *FGFR1* gene encodes the fibroblast growth factor receptor 1 protein, a crucial cell surface receptor.
FGFR1 is located on the short (p) arm of chromosome 8, at band 8p11.23. Arm ratio per GRCh38 - banding schematic.
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Overview
The *FGFR1* gene, or fibroblast growth factor receptor 1, is a key component in human biology, instructing the production of a protein that functions as a cell surface receptor. This receptor is one of a family of four fibroblast growth factor receptors, all of which are central to regulating numerous cellular activities [PMID:23000632]. These activities include cell division, growth control, cell maturation, blood vessel formation (angiogenesis), wound healing, and intricate processes during embryonic development.
The *FGFR1* protein acts as a transmembrane protein, meaning it spans the cell's outer membrane. This positioning allows an exterior portion of the protein to interact with external signalling molecules, specifically fibroblast growth factors (FGFs). Upon binding to an FGF, the receptor initiates a cascade of internal cellular reactions that instruct the cell to adapt or acquire new functions [PMID:23000632]. This signalling is crucial for the proper development and growth of various body parts, including the brain, the bones forming the skull and face (craniofacial bones), hand and foot bones, and the long bones of the limbs.
What the gene does
The *FGFR1* gene is responsible for creating the fibroblast growth factor receptor 1 protein, a pivotal membrane-spanning protein. This protein acts as a cellular receiver, with one end extending outside the cell to bind to fibroblast growth factors (FGFs), and the other projecting inside to transmit signals [PMID:23000632]. This interaction initiates a critical series of biochemical events within the cell, enabling it to respond to its environment and undergo specific changes.
The signalling pathway regulated by *FGFR1* is highly significant for the formation, survival, and directed movement (migration) of neuronal cells in various brain regions. It appears particularly essential for neurons that produce gonadotropin-releasing hormone (GnRH). GnRH is vital for controlling the production of other hormones that orchestrate sexual development both before birth and throughout puberty, influencing the healthy functioning of the ovaries and testes.
Furthermore, *FGFR1* signalling is understood to contribute to the processing of olfactory cues by specialised neurons involved in the sense of smell. Its broad involvement underscores its significance in diverse developmental and physiological processes [PMID:23000632, PMID:27568571].
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Chromosome location
The *FGFR1* gene is located on chromosome 8, specifically at position 8p11.23. This region of the human genome contains the genetic instructions for the fibroblast growth factor receptor 1 protein. The gene is officially recognised with the HGNC ID HGNC:3688 and its protein product has the UniProt accession P11362.
Protein structure
The fibroblast growth factor receptor 1 protein, encoded by the *FGFR1* gene, spans 822 amino acids and exhibits a complex domain architecture typical of receptor tyrosine kinases. The extracellular portion includes three Ig-like C2-type domains: the first from amino acids 25-119, the second from amino acids 158-246, and the third from amino acids 255-357. Within the second Ig-like C2-type domain, a heparin-binding region is located from amino acids 160-177. Additionally, two disordered regions are present, one between amino acids 120-154 and another towards the C-terminus from amino acids 778-822. The intracellular part of the protein features a crucial Protein kinase domain, essential for its signalling function, located between amino acids 478-767.
Key variants
Variants within the *FGFR1* gene can alter the structure or function of the fibroblast growth factor receptor 1 protein, potentially disrupting the intricate signalling pathways it orchestrates. Depending on their nature and location, these genetic changes can lead to a range of medical conditions affecting development, hormone regulation, and cellular proliferation. The inheritance pattern for conditions associated with *FGFR1* variants can vary, highlighting the complex genetic mechanisms involved. Comprehensive genetic analysis is crucial for understanding the specific implications of identified *FGFR1* variants.
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.1029G>A | p.Ala343= | Pathogenic/Likely pathogenic | ★★☆☆ | FGFR1-related disorder |
c.1037_1038del | p.Ser346fs | Pathogenic/Likely pathogenic | ★★☆☆ | Delayed puberty |
c.1042G>A | p.Gly348Arg | Pathogenic | ★★☆☆ | Hypogonadotropic hypogonadism 2 with anosmia |
c.1141T>C | p.Cys381Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Osteoglophonic dysplasia |
c.1468G>A | p.Gly490Arg | Pathogenic | ★★☆☆ | not provided |
c.154C>T | p.Gln52Ter | Pathogenic | ★★☆☆ | Hypogonadotropic hypogonadism 2 with or without anosmia |
c.1589C>G | p.Ser530Ter | Pathogenic | ★★☆☆ | Hypogonadotropic hypogonadism 2 with or without anosmia |
c.1601TGA[1] | p.Met535del | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1638C>A | p.Asn546Lys | Pathogenic | ★★☆☆ | Encephalocraniocutaneous lipomatosis |
c.1825C>T | p.Arg609Ter | Pathogenic | ★★☆☆ | Hypogonadotropic hypogonadism 2 with anosmia |
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 *FGFR1* gene are associated with a spectrum of conditions, often involving developmental abnormalities and hormonal imbalances. These include Kallmann syndrome, characterised by impaired sexual development and sense of smell, and Hartsfield syndrome, which involves brain malformations and hand/foot abnormalities. Other conditions linked to *FGFR1* variants are 8p11 myeloproliferative syndrome, a type of blood cancer; encephalocraniocutaneous lipomatosis, a rare condition with noncancerous tumours and other abnormalities in brain, eyes, and skin; and osteoglophonic dysplasia, involving abnormal bone growth. The specific condition that develops often depends on the type and location of the *FGFR1* variant.
No disease links recorded for this gene in our reference set.
UK clinical status
The *FGFR1* gene is highly relevant in the context of genetic testing within the NHS, being featured on numerous diagnostic panels. It has a 'green' status on several PanelApp entries, indicating strong evidence for its association with specific conditions and its utility in clinical diagnostics. These include panels for Common craniosynostosis syndromes (R99), Rare syndromic craniosynostosis or isolated multisuture synostosis (R100), Foetal anomalies (R21), Holoprosencephaly (R85), Hydrocephalus (R86), Pituitary hormone deficiency (R159), and Hypogonadotropic hypogonadism (GMS) (R148). This widespread inclusion underscores the gene's established role in diagnosing a range of developmental and endocrine conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a balanced and healthy lifestyle generally supports overall well-being, which is beneficial for individuals with or without genetic predispositions. For conditions associated with *FGFR1* variants, specific lifestyle changes are not typically prescribed as a primary treatment. However, general recommendations such as a nutritious diet, regular physical activity, and avoiding smoking and excessive alcohol consumption are universally encouraged for their broad health benefits. For conditions like craniosynostosis or hypogonadotropic hypogonadism, lifestyle support would typically be part of a broader, medically managed treatment plan.
Supplement considerations
There is no conclusive evidence to suggest that specific dietary supplements can prevent or treat conditions associated with *FGFR1* gene variants. Any decision to take supplements should be carefully considered and discussed with a healthcare professional to ensure safety and appropriateness, particularly given the complex nature of the conditions linked to *FGFR1* gene function. General nutritional guidelines often recommend obtaining vitamins and minerals through a balanced diet.
Frequently asked questions
What does the *FGFR1* gene do?
The *FGFR1* gene provides instructions for making the fibroblast growth factor receptor 1 protein, which plays a crucial role in cell signalling, growth, development, and differentiation by binding to fibroblast growth factors.
What conditions are associated with *FGFR1* gene variants?
Variants in the *FGFR1* gene are associated with conditions such as Kallmann syndrome, Hartsfield syndrome, 8p11 myeloproliferative syndrome, encephalocraniocutaneous lipomatosis, and osteoglophonic dysplasia, often affecting development, hormone regulation, and cell growth.
How is *FGFR1* involvement diagnosed in the UK?
In the UK, *FGFR1* is included on several NHS genetic testing panels, such as those for craniosynostosis, foetal anomalies, hypogonadotropic hypogonadism, and pituitary hormone deficiency, indicating its established role in clinical diagnostics.
Can lifestyle changes or supplements address *FGFR1*-related conditions?
Currently, there is no conclusive evidence that specific lifestyle changes or dietary supplements can prevent or treat conditions directly caused by *FGFR1* gene variants. Any health decisions, including taking supplements, should be discussed with a healthcare professional.
Is the *FGFR1* gene linked to cancer?
Yes, the *FGFR1* gene is involved in 8p11 myeloproliferative syndrome, a type of blood cancer, and has also been associated with noncancerous tumours in encephalocraniocutaneous lipomatosis.
References
- Bennett JT, Tan TY, Alcantara D. Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis. American journal of human genetics. 2016. PMID: 26942290
- Jiang T, Gao G, Fan G. FGFR1 amplification in lung squamous cell carcinoma: a systematic review with meta-analysis. Lung cancer (Amsterdam, Netherlands). 2015. PMID: 25433983
- Chokdeemboon C, Mahatumarat C, Rojvachiranonda N. FGFR1 and FGFR2 mutations in Pfeiffer syndrome. The Journal of craniofacial surgery. 2013. PMID: 23348274
- Simonis N, Migeotte I, Lambert N. FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly. Journal of medical genetics. 2013. PMID: 23812909
- Villanueva C, de Roux N. FGFR1 mutations in Kallmann syndrome. Frontiers of hormone research. 2010. PMID: 20389085
- Kim SH, Hu Y, Cadman S. Diversity in fibroblast growth factor receptor 1 regulation: learning from the investigation of Kallmann syndrome. Journal of neuroendocrinology. 2008. PMID: 18034870
- Elbauomy Elsheikh S, Green AR, Lambros MB. FGFR1 amplification in breast carcinomas: a chromogenic in situ hybridisation analysis. Breast cancer research : BCR. 2007. PMID: 17397528
- Farrow EG, Davis SI, Mooney SD. Extended mutational analyses of FGFR1 in osteoglophonic dysplasia. American journal of medical genetics. Part A. 2006. PMID: 16470795
- Pitteloud N, Acierno JS Jr, Meysing A. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proceedings of the National Academy of Sciences of the United States of America. 2006. PMID: 16606836
- White KE, Cabral JM, Davis SI. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. American journal of human genetics. 2005. PMID: 15625620
- Dodé C, Levilliers J, Dupont JM. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nature genetics. 2003. PMID: 12627230
- Macdonald D, Reiter A, Cross NC. The 8p11 myeloproliferative syndrome: a distinct clinical entity caused by constitutive activation of FGFR1. Acta haematologica. 2002. PMID: 11919391
- Adam MP, Bick S, Mirzaa GM. Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency. 1993. PMID: 20301509