Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia
Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia
复制标题
DOI：
10.1016/j.bbadis.2008.11.010
复制
发表时间：
2009-02-01
影响因子：
6.2
通讯作者：
Legeai-Mallet, Laurence
中科院分区：
文献类型：
--
作者：
Pannier, Stephanie;Couloigner, Vincent;Legeai-Mallet, Laurence
成纤维细胞生长因子受体3 （FGFR3）是骨骼发育的关键调节因子，FGFR3的激活突变会导致骨骼发育不良，包括软骨发育不全、软骨发育不全和嗜盐性发育不良。将Y367C突变引入小鼠基因组，该突变与人类Y373C thanatoporic dysplasia I型（TDI）突变相对应，导致侏儒症，其骨骼表型与人类软骨发育不良非常相似。为了研究激活Fgfr3 Y367C突变在听觉功能中的作用，我们检测了杂合突变Fgfr3（Y367C/+）小鼠的中耳和内耳。突变Fgfr3（Y367C/+）小鼠表现出完全渗透性耳聋，在所有测试频率下，听觉脑脊髓反应阈值显著升高。内耳缺损主要与Corti器官中柱细胞或修饰的支持细胞数量增加有关。Fgfr3（Y367C/+）小鼠模型中的听力损失证明了Fgrr3在内耳发育中的关键作用，并为Fgfr3突变在软骨发育不良中的生物学后果提供了新的见解。(c) 2008 Elsevier B.V.版权所有
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 brainstern 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 Fgrr3 in the development of the inner ear and provides novel insight on the biological consequences of FGFR3 mutations in chondrodysplasia. (c) 2008 Elsevier B.V. All rights reserved.