R448 – Phex Mutation Causes Sensorineural Deafness in Mice

Abstract

Problem Pug is an ENU mutated mouse model for X-linked dominant hypophosphatemic rickets (XLH) in human. Mapping and sequence analysis revealed that Pug mutation is a unique Phe-to-Ser transition at amino acid 80 of PHEX protein leading to the loss of Phex function. Patients with XLH and Pug mutant mice exhibit abnormal phenotypes including growth retardation, hypophosphatemia and osteomalacia. In addition, hearing impairment was also found in some hypophosphatemic mouse models and patients. Here, we used the Pug mutant mice to study the role of Phex gene in the pathology of hearing impairment. Methods Auditory brainstem responses(ABR) to click and 8,16,32kHz stimuli were employed to measure pug mice of 1–8 months old. Serial sections were used to detect the abnormalities involving the temporal bone, stria vascularis, the organ of Corti, spiral ganglion cells, and scanning electron microscopy was performed to exam the basilar membrane of pug mice. Results Auditory brainstem responses test showed that Pug mice have elevated hearing thresholds. Histology analysis demonstrated a thickened temporal bone with many interspersed areas of nonmineralization surrounding the mutant cochlea and decreased numbers of neuronal processes in the organ of Corti, mostly in basal turns. Furthermore, abnormal stereocilia of inner and outer hair cells of the Corti organ were identified by scanning electron microscopy. Inner and outer hair cells were also greatly reduced in Pug mice. Conclusion The impaired hearing function and the morphological abnormalities of inner ears are induced by the mutation of Phex gene. Significance Pug mice have structural and functional defects in the inner ear and may serve as a new disease model of sensorineural deafness. Support This work was supported by the ground of JiangSu Province Femouse Doctor Project(RC2007010).