Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia

Abstract

Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of skeletal development and activating mutations in FGFR3 cause skeletal dysplasias, including hypochondroplasia, achondroplasia and thanatophoric dysplasia. The introduction of the Y367C mutation corresponding to the human Y373C thanatophoric dysplasia type I (TDI) mutation into the mouse genome, resulted in dwarfism with a skeletal phenotype remarkably similar to that of human chondrodysplasia. To investigate the role of the activating Fgfr3 Y367C mutation in auditory function, the middle and inner ear of the heterozygous mutant Fgfr3(Y367C/+) mice were examined. The mutant Fgfr3(Y367C/+) mice exhibit fully penetrant deafness with a significantly elevated auditory brainstem response threshold for all frequencies tested. The inner ear defect is mainly associated with an increased number of pillar cells or modified supporting cells in the organ of Corti. Hearing loss in the Fgfr3(Y367C/+) mouse model demonstrates the crucial role of Fgfr3 in the development of the inner ear and provides novel insight on the biological consequences of FGFR3 mutations in chondrodysplasia.

Hearing Loss in Syndromic Craniosynostoses: Introduction and Consideration of Mechanisms

“…A study of a mouse model of chondroplasia ( Fgfr3 Y367C mutation) revealed hearing loss and, interestingly, as in the mouse that lacks Fgfr3 completely, the only inner ear defect observed in this mouse was an increased number of pillar cells and modified supporting cells in the organ of Corti (Pannier et al, 2009). …”

Fibroblast growth factor signaling in skeletal development and disease

“…The N540K mutation causing hypochondroplasia is a weak gain-of-function mutation, and mutations causing achondroplasia and thantophoric dysplasia result in progressively stronger activation and, in the case of the R248C mutation, ligand-independent constitutive activation. FGFR3 is expressed prominently in proliferating and prehypertrophic chondrocytes in the growth plate, and activation of FGFR3 results in phenotypes that include decreased chondrocyte proliferation, impaired hypertrophic differentiation, and increased apoptosis (discussed below; Legeai-Mallet et al 1998Naski et al 1998;Wang et al 1999Wang et al , 2001Krejci et al 2008b;Pannier et al 2009). …”

RECENT RESEARCH ON THE GROWTH PLATE: Advances in fibroblast growth factor signaling in growth plate development and disorders

“…Mice mimicking human TDII-carrying the Fgfr3 K644E mutation exhibit enhanced chondrocyte proliferation during the early embryonic skeletal development and reduced hypertrophic chondrocytes throughout the embryonic stage (Li et al 1999, Iwata et al 2000. The Fgfr3 K644M mutation causes severe dwarfism in mice (Iwata et al 2001) and the Y367C mutation causes chondrodysplasia, hearing loss, and inner ear defects in mice (Pannier et al 2009). The above data indicate that FGFR3 negatively regulates the proliferation and differentiation of chondrocytes.…”