title: A mouse model with postnatal endolymphatic hydrops and hearing loss.
abstract: Endolymphatic hydrops (ELH), hearing loss and neuronal degeneration occur together in a variety of clinically significant disorders, including Meniere's disease (MD). However, the sequence of these pathological changes and their relationship to each other are not well understood. In this regard, an animal model that spontaneously develops these features postnatally would be useful for research purposes. A search for such a model led us to the Phex Hyp-Duk mouse, a mutant allele of the Phex gene causing X-linked hypophosphatemic rickets. The hemizygous male (Phex Hyp-Duk/Y) was previously reported to exhibit various abnormalities during adulthood, including thickening of bone, ELH and hearing loss. The reported inner-ear phenotype was suggestive of progressive pathology and spontaneous development of ELH postnatally, but not conclusive. The main focuses of this report are to further characterize the inner ear phenotype in Phex Hyp-Duk/Y mice and to test the hypotheses that (a) the Phex Hyp-Duk/Y mouse develops ELH and hearing loss postnatally, and (b) the development of ELH in the Phex Hyp-Duk/Y mouse is associated with obstruction of the endolymphatic duct (ED) due to thickening of the surrounding bone. Auditory brainstem response (ABR) recordings at various times points and histological analysis of representative temporal bones reveal that Phex Hyp-Duk/Y mice typically develop adult onset, asymmetric, progressive hearing loss closely followed by the onset of ELH. ABR and histological data show that functional degeneration precedes structural degeneration. The major degenerative correlate of hearing loss and ELH in the mutants is the primary loss of spiral ganglion cells. Further, Phex Hyp-Duk/Y mice develop ELH without evidence of ED obstruction, supporting the idea that ELH can be induced by a mechanism other than the blockade of longitudinal flow of endolymphatic fluid, and occlusion of ED is not a prerequisite for the development of ELH in patients.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Case Western Reserve University, University Hospitals-Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Cliff A
authors.initials: CA
authors.lastname: Megerian
authors.forename: Maroun T
authors.initials: MT
authors.lastname: Semaan
authors.forename: Saba
authors.initials: S
authors.lastname: Aftab
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Kisley
authors.forename: Qing Yin
authors.initials: QY
authors.lastname: Zheng
authors.forename: Karen S
authors.initials: KS
authors.lastname: Pawlowski
authors.forename: Charles G
authors.initials: CG
authors.lastname: Wright
authors.forename: Kumar N
authors.initials: KN
authors.lastname: Alagramam
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007758:Ear, Inner / Q000473:pathology / Q000503:physiopathology; D004711:Endolymphatic Duct / Q000473:pathology / Q000503:physiopathology; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008575:Meniere Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D053402:PHEX Phosphate Regulating Neutral Endopeptidase / Q000235:genetics*; D010641:Phenotype
chemical_list: D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506232:Phex protein, mouse