title: Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human.
abstract: Sensorineural hearing loss affects the quality of life and communication of millions of people, but the underlying molecular mechanisms remain elusive. Here, we identify mutations in Gipc3 underlying progressive sensorineural hearing loss (age-related hearing loss 5, ahl5) and audiogenic seizures (juvenile audiogenic monogenic seizure 1, jams1) in mice and autosomal recessive deafness DFNB15 and DFNB95 in humans. Gipc3 localizes to inner ear sensory hair cells and spiral ganglion. A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents. Magnitude and temporal progression of wave I amplitude of afferent neurons correlate with susceptibility and resistance to audiogenic seizures. The Gipc3(343A) allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons. Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells.
authors.affiliation: Section on Neurogenetics, Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, USA.
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Charizopoulou
authors.forename: Andrea
authors.initials: A
authors.lastname: Lelli
authors.forename: Margit
authors.initials: M
authors.lastname: Schraders
authors.forename: Kausik
authors.initials: K
authors.lastname: Ray
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hildebrand
authors.forename: Arabandi
authors.initials: A
authors.lastname: Ramesh
authors.forename: C R Srikumari
authors.initials: CR
authors.lastname: Srisailapathy
authors.forename: Jaap
authors.initials: J
authors.lastname: Oostrik
authors.forename: Ronald J C
authors.initials: RJ
authors.lastname: Admiraal
authors.forename: Harold R
authors.initials: HR
authors.lastname: Neely
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Latoche
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: John K
authors.initials: JK
authors.lastname: Northup
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Holt
authors.forename: Konrad
authors.initials: K
authors.lastname: Noben-Trauth
mesh_terms: D000161:Acoustic Stimulation; D048868:Adaptor Proteins, Signal Transducing; D000704:Analysis of Variance; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D003433:Crosses, Genetic; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006198:Hair Cells, Auditory / Q000378:metabolism; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006320:Hearing Tests; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D040542:Mechanotransduction, Cellular / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C452600:GIPC3 protein, human