A number of skeletal and developmental diseases have been shown to arise as a result of mutations in the FGFR1, 2 and 3 genes. These include dwarfism syndromes (achondroplasia, hypochondroplasia and the neonatal lethal disorders thanatophoric dysplasia I and II), as well as craniosynostosis disorders such as Pfeiffer, Apert, Crouzon, Jackson-Weiss and Muenke syndromes (reviewed in Webster and Donoghue 1997; Burke, 1998, Cunningham, 2007; Harada, 2009). These mutations fall into four general regions of the receptor: a) the immunoglobulin (Ig)-like domain II-III linker region, b) the alternatively spliced second half of the Ig III domain, c) the transmembrane domain and d) the tyrosine kinase domain (reviewed in Webster and Donoghue, 1997). With the exception of mutations in class b), which affect only the relevant splice variant, these mutations may be present in either the 'b' or 'c' isoforms. These activating mutations affect FGFR function by altering or expanding the ligand-binding range of the receptors (see for instance Ibrahimi, 2004a), by promoting ligand-independent dimerization (for instance, Galvin,1996; Neilson and Friesel, 1996; d'Avis,1998) or by increasing the activity of the kinase domain (for instance, Webster, 1996; Naski, 1996; Tavormina, 1999; Bellus, 2000). Thus, a number of the point mutations found in FGFR receptors alter their activity without altering their intrinsic kinase activity. Many of the mutations that promote constitutive dimerization do so by creating or removing cysteine residues; the presence of an unpaired cysteine in the receptor is believed to promote dimerization through the formation of intramolecular disulphide bonds (Galvin, 1996; Robertson, 1998). Paralogous mutations at equivalent positions have been identified in more than one FGF receptor, sometimes giving rise to different diseases. For instance, mutation of the highly conserved FGFR2 Ser252-Pro253 dipeptide in the region between the second and third Ig domain is responsible for virtually all cases of Apert Syndrome (Wilkie, 1995), while paralogous mutations in FGFR1 (S252R) and FGFR3 (P250R) are associated with Pfeiffer and Crouzon syndromes, respectively (Bellus, 1996). FGFR4 is unique in that mutations of this gene are not known to be associated with any developmental disorders.
Recently, many of the same activating mutations in the FGFR genes that have been characterized in skeletal and developmental disorders have begun to be identified in a range of cancers (reviewed in Turner and Gross, 2010; Greulich and Pollock, 2011; Wesche, 2011). The best established link between a somatic mutation of an FGFR and the development of cancer is in the case of FGFR3, where 50% of bladder cancers have mutations in the FGFR3 coding sequence. Of these mutations, which largely match the activating mutations seen in thanatophoric dysplasias, over half occur at a single residue (S249C) (Cappellen, 1999; van Rhijn, 2002). Activating mutations have also been identified in the coding sequences of FGFR1, 2 and 4 (for review, see Wesche, 2011)
In addition to activating point mutations, the FGFR1, 2 and 3 genes are subject to misregulation in cancer through gene amplification and translocation events, which are thought to lead to overexpression and ligand-independent dimerization (Weiss, 2010; Turner, 2010; Kunii, 2008; Takeda, 2007; Chesi, 1997; Avet-Loiseau, 1998; Ronchetti, 2001). It is important to note, however, that in each of these cases, the amplification or translocation involve large genomic regions encompassing additional genes, and the definitive roles of the FGFR genes in promoting oncogenesis has not been totally established. In the case of FGFR1, translocation events also give rise to FGFR1 fusion proteins that contain the intracellular kinase domain of the receptor fused to a dimerization domain from the partner gene. These fusions, which are expressed in a pre-leukemic myeloproliferative syndrome, dimerize constitutively based on the dimerization domain provided by the fusion partner and are constitutively active (reviewed in Jackson, 2010).