FGFR1
Gene loci
- Chromosome 8p11.23.
Normal function
- FGFR1 encodes a receptor tyrosine kinase involved in cell division, growth, maturation, blood vessel formation, wound healing, and embryonic development.
- It interacts with fibroblast growth factors (FGFs) to transduce signals regulating these processes.
- Essential for gastrulation, neurulation, and mesodermal development.
Effects of mutations
- Malformation
- Loss-of-function mutations cause Kallmann syndrome with skeletal malformations like hemivertebra, butterfly vertebra, oligodactyly, and metacarpal fusion.
- Tumour
- Gain-of-function or fusions lead to constitutive activation, promoting cancer via PI3K/AKT, Ras/ERK, STAT pathways.
- Extraventricular neurocytoma
- FGFR1 alteration (mostly FGFR1::TACC1 fusion)
- Dysembryoplastic neuroepithelial tumour (DNET)
- FGFR1 internal tandem duplication [ITD], fusion, missense mutation
- Rosette forming glioneuronal tumour (RGNT)
- Diffuse low-grade glioma, MAPK pathway-altered
- FGFR1 tyrosine kinase domain (TDK)-duplicated
- Rearrangements in 8p11 myeloproliferative syndrome progress to acute myeloid leukemia.
FGFR2
Gene loci
- Chromosome 10q26.
Normal function
- Encodes a receptor tyrosine kinase that binds FGFs, regulating cell proliferation, differentiation, and development.
- Essential for embryonic development, epithelial-mesenchymal interactions, bone growth.
Effects of mutations
- Malformation
- Gain-of-function mutations cause ligand-independent activation, leading to craniosynostosis and skeletal dysplasias.
- Apert syndrome (S252W, P253R).
- Crouzon syndrome, Pfeiffer syndrome, Jackson-Weiss syndrome.
- Tumour
- Ligand-binding domain mutations alter specificity, activating abnormal pathways.
- Polymorphous low-grade neuroepithelial tumour of the young (PLNTY)
- Fusion transcript involving FGFR2 (including the kinase domain) joined with CTNNA3 (to include the entirety of its C‐terminal dimerization domain) [22, 23]; the resultant fusion is thought to lead to homodimerization and autophosphorylation of FGFR2 and downstream MAPK/PI3K/mTOR pathway activation
FGFR3
Gene loci
- Chromosome 4p16.3.
Normal function
- Receptor tyrosine kinase binding FGFs, inhibiting bone growth, regulating cell proliferation and differentiation.
- Expressed in cartilage, brain, intestine, kidneys.
Effects of mutations
- Activating mutations cause excessive signaling, inhibiting endochondral ossification.
- Kinase domain mutations lead to constitutive activation.
Clinical associations
- Achondroplasia (G380R).
- Thanatophoric dysplasia types I/II, hypochondroplasia, Crouzon with acanthosis nigricans.
- Bladder cancer (S249C, low-grade).
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