Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice

Abstract

Several gain-of-function mutations in a receptor tyrosine kinase, fibroblast growth factor receptor 3 (FGFR3), cause dwarfism in humans. Two particularly severe dwarfisms, thanatophoric dysplasia type II (TDII) and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), are associated with glutamic acid (E) and methionine (M) substitutions at the K650 residue in the kinase domain. TDII is lethal at birth, whereas most of the SADDAN patients survive the perinatal period. However, FGFR3 with the SADDAN mutation is more activated than FGFR3 with the TDII mutation in vitro. To find out whether the K650M mutation also causes the SADDAN phenotype, we introduced the corresponding point mutation (K644M) into the mouse Fgfr3 gene. Heterozygous mutant mice show a phenotype similar to human SADDAN, e.g. the majority of the SADDAN mice survive the perinatal period. This suggests that the survival of SADDAN patients is indeed attributed to the K650M mutation in FGFR3. The long bone abnormalities in SADDAN mice are milder than the TDII model. In addition, overgrowth of the cartilaginous tissues is observed in the rib cartilage, trachea and nasal septum. The FGF ligand at the low concentration differentially activates Map kinase in primary chondrocyte cultures from wild-type and SADDAN mice. Comparisons of the molecular bases of the phenotypic differences in SADDAN and TDII mice may increase our understanding of the factors that influence the severity in these two related skeletal dysplasias.

Fibroblast growth factor signaling in skeletal development and disease

“…Mice lacking Fgf18 show decreased chondrocyte proliferation in more distal skeletal elements (Liu et al 2007). This phenotype is consistent with FGF9 and FGF18 signaling to FGFR3 and the promitogenic properties of FGFR3 on immature chondrocytes (Iwata et al 2000(Iwata et al , 2001Hung et al 2007). At later stages of development, Fgf9 −/− and Fgf18 −/− mice show an expansion of the femoral hypertrophic chondrocyte zone, a phenotype that is consistent with FGFR3 functioning to suppress chondrocyte proliferation and differentiation in the mature growth plate (Liu et al 2002;Ohbayashi et al 2002;Hung et al 2007).…”

“…FGFR3 signaling is mitogenic for immature proliferating chondrocytes and is likely activated by FGF9 and FGF18, which are expressed in adjacent mesenchyme ( Fig. 1; Iwata et al 2000Iwata et al , 2001Liu et al 2002Liu et al , 2007Ohbayashi et al 2002;Hung et al 2007;Havens et al 2008).…”

“…In early embryonic stages of skeletal development, during establishment of the growth plate, FGFR3 has promitogenic activity in chondrocytes (Iwata et al 2000(Iwata et al , 2001Havens et al 2008). However, following formation of the secondary ossification center and throughout postnatal skeletal growth, FGFR3 signaling functions to inhibit chondrogenesis, primarily acting on proliferating chondrocytes and their differentiation to prehypertrophic and hypertrophic chondrocytes (Colvin et al 1996;Deng et al 1996).…”

FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease

“…This relationship provides the first evidence for negative regulation of chondrogenesis by FGFR3. This genotypephenotype correlation is supported by several mouse models harboring activating mutations in FGFR3 (Table 1; Chen et al , 2001Li et al 1999;Wang et al 1999;Segev et al 2000;Iwata et al 2001).…”

Frontal nasal prominence expression driven by Tcfap2a relies on a conserved binding site for STAT proteins

“…FGFR3-related skeletal defects arise from both altered proliferation of chondrocytes in the growth plate and premature ossification (Ornitz and Marie, 2002;Chen and Deng, 2005;L'Hote and Knowles, 2005;Ornitz, 2005). In contrast to the general inhibitory effect of FGFR3 on post-natal long bone growth, a SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) FGFR3 mouse model exhibited overgrowth of the nasal septum and a high incidence of dental malocclusion (Iwata et al, 2001). These phenotypes are reminiscent of defects observed in FKO and Tcfap2a ϩ/Ϫ mice (Zhang et al, 1996;Nottoli et al, 1998;Nelson and Williams, 2004).…”