title: A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation.
abstract: The gene causative for the human nonsyndromic recessive form of deafness DFNB22 encodes otoancorin, a 120-kDa inner ear-specific protein that is expressed on the surface of the spiral limbus in the cochlea. Gene targeting in ES cells was used to create an EGFP knock-in, otoancorin KO (Otoa(EGFP/EGFP)) mouse. In the Otoa(EGFP/EGFP) mouse, the tectorial membrane (TM), a ribbon-like strip of ECM that is normally anchored by one edge to the spiral limbus and lies over the organ of Corti, retains its general form, and remains in close proximity to the organ of Corti, but is detached from the limbal surface. Measurements of cochlear microphonic potentials, distortion product otoacoustic emissions, and basilar membrane motion indicate that the TM remains functionally attached to the electromotile, sensorimotor outer hair cells of the organ of Corti, and that the amplification and frequency tuning of the basilar membrane responses to sounds are almost normal. The compound action potential masker tuning curves, a measure of the tuning of the sensory inner hair cells, are also sharply tuned, but the thresholds of the compound action potentials, a measure of inner hair cell sensitivity, are significantly elevated. These results indicate that the hearing loss in patients with Otoa mutations is caused by a defect in inner hair cell stimulation, and reveal the limbal attachment of the TM plays a critical role in this process.
authors.affiliation: School of Life Sciences,  University of Sussex, Falmer, Brighton BN1 9QG,  United Kingdom.
authors.forename: Andrei N
authors.initials: AN
authors.lastname: Lukashkin
authors.forename: P Kevin
authors.initials: PK
authors.lastname: Legan
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Weddell
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Lukashkina
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Goodyear
authors.forename: Lindsey J
authors.initials: LJ
authors.lastname: Welstead
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Russell
authors.forename: Guy P
authors.initials: GP
authors.lastname: Richardson
mesh_terms: D000161:Acoustic Stimulation; D000200:Action Potentials; D000818:Animals; D001489:Basilar Membrane / Q000473:pathology / Q000503:physiopathology; D003051:Cochlea / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D058851:GPI-Linked Proteins / Q000235:genetics; D018390:Gene Targeting; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006199:Hair Cells, Auditory, Inner / Q000473:pathology*; D034381:Hearing Loss / Q000473:pathology / Q000503:physiopathology; D006319:Hearing Loss, Sensorineural / Q000473:pathology*; D006801:Humans; D051379:Mice; D008857:Microscopy, Interference; D016254:Mutagenesis, Insertional / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D013680:Tectorial Membrane / Q000473:pathology / Q000503:physiopathology
chemical_list: D058851:GPI-Linked Proteins; C486746:Otoa protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins