title: 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.
authors.affiliation: INSERM U781-Université Paris Descartes-Hôpital Necker-Enfants Malades-149 rue de Sèvres-75015, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Pannier
authors.forename: Vincent
authors.initials: V
authors.lastname: Couloigner
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.forename: Monique
authors.initials: M
authors.lastname: Elmaleh-Bergès
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Raymond
authors.initials: R
authors.lastname: Romand
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
mesh_terms: D000818:Animals; D002806:Chondrodysplasia Punctata / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D034381:Hearing Loss / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D006579:Heterozygote; D007759:Labyrinth Diseases / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D014443:Tyrosine; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3