Sixteen years and counting: The current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias

Abstract

In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the FGFR3 receptor tyrosine kinase account for the common genetic form of dwarfism in humans, achondroplasia. Other conditions soon followed, with the list of human disorders caused by FGFR3 mutations now reaching at least 10. An array of vastly different diagnoses is caused by similar mutations in FGFR3, including syndromes affecting skeletal development (hypochondroplasia, achondroplasia, thanatophoric dysplasia), skin (epidermal nevi, seborrhaeic keratosis, acanthosis nigricans) and cancer (multiple myeloma, prostate and bladder carcinoma, seminoma). Despite many years of research, several aspects of FGFR3 function in disease remain obscure or controversial. As FGFR3-related skeletal dysplasias are caused by growth attenuation of the cartilage, chondrocytes appear to be unique in their response to FGFR3 activation. However, the reasons why FGFR3 inhibits chondrocyte growth while causing excessive cellular proliferation in cancer are not clear. Likewise, the full spectrum of molecular events by which FGFR3 mediates its signaling is just beginning to emerge. This article describes the challenging journey to unravel the mechanisms of FGFR3 function in skeletal dysplasias, the extraordinary cellular manifestations of FGFR3 signaling in chondrocytes, and finally, the progress towards therapy for achondroplasia and cancer.

Fibroblast growth factor signaling in skeletal development and disease

“…Following this initial discovery, many mutations have been identified in FGFR1-3 in related skeletal dwarfism syndromes, craniosynostosis syndromes, and skeletal overgrowth syndromes (Ornitz and Itoh 2015). The clinical and genetic features of these diseases have been extensively reviewed (Vajo et al 2000;Ornitz and Marie 2002;Chen and Deng 2005;Marie et al 2005;Ornitz 2005;Melville et al 2010;Johnson and Wilkie 2011;Foldynova-Trantirkova et al 2012;Krejci 2014).…”

“…Skeletal drawfism in hypochondroplasia, achondroplasia, and thanatophoric dysplasia results from increased FGFR3 signaling in proliferating and hypertrophic chondrocytes (Foldynova-Trantirkova et al 2012). For achondroplasia, in which affected individuals attain adult heights that are well below the fifth percentile, pharmacological therapy promises to offer an alternative to painful and costly surgical therapies that are currently used to increase height and correct disproportional bone growth.…”

Molecular Analysis of a Case of Thanatophoric Dysplasia Reveals Two de Novo FGFR3 Missense Mutations located in Cis

“…22 Each of the mutations identified in our fetus is located within the first portion of the split intra-cellular tyrosine kinase domain. 23 It has been recognised that the activation of FGFR3 caused by substitutions within the tyrosine kinase domain is due to a mechanism that mirrors the conformational changes that are normally a result of ligand-mediated FGFR3 dimerisation and autophosphorylation. 23,24 Double mutation alleles have been reported in association with a range of disorders, often complicating genotype-phenotype correlations.…”

“…23 It has been recognised that the activation of FGFR3 caused by substitutions within the tyrosine kinase domain is due to a mechanism that mirrors the conformational changes that are normally a result of ligand-mediated FGFR3 dimerisation and autophosphorylation. 23,24 Double mutation alleles have been reported in association with a range of disorders, often complicating genotype-phenotype correlations. 25,26 It is probable that the basis of the severe phenotype seen in our case, in contrast to the phenotype that results from the Asn540Lys mutation alone or in combination with Gly380Arg, is related to the 'double-hit' effect of two mutations both acting in this critical region of the protein.…”

A novel variant of FGFR3 causes proportionate short stature

“…Mutations in FGFR3 have been identified in several skeletal disorders (1), and almost all reported FGFR3 mutations to date cause constitutive activation of the receptor, resulting in impaired endochondral bone growth (2). bones, narrowing (or failure to widen) of the lumbar interpedicular distances, short femoral neck, and square ilia (3).…”