A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C

Sound transduction occurs in the hair bundle, the apical compartment of sensory hair cells in the inner ear. The hair bundle is formed of actin-based stereocilia aligned in rows of graded heights. It was previously shown that the GNAI-GPSM2 complex is part of a developmental blueprint that defines the polarized organization of the apical cytoskeleton in hair cells, including stereocilia distribution and elongation. Here we report a novel and critical role for Multiple PDZ domain (MPDZ) protein during apical hair cell morphogenesis. We show that MPDZ is enriched at the hair cell apical membrane along with MAGUK p55 subfamily member 5 (MPP5/PALS1) and the Crumbs protein CRB3. MPDZ is required there to maintain the proper segregation of apical blueprints proteins, including GNAI-GPSM2. Loss of the blueprint coincides with misaligned stereocilia placement in Mpdz mutant hair cells, and results in permanently misshapen hair bundles. Graded molecular and structural defects along the cochlea can explain the profile of hearing loss in Mpdz mutants, where deficits are most severe at high frequencies.

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Researchers restore hearing in noise-deafened mouse: NIDCD-supported researchers use drug to grow new sensory hair cells in the inner ear

PsycEXTRA Dataset ◽

10.1037/e522812013-001 ◽

2013 ◽

Keyword(s):

Inner Ear ◽

Hair Cells ◽

Sensory Hair ◽

Hearing In Noise ◽

Sensory Hair Cells

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Cod106, a novel synaptic protein expressed in sensory hair cells of the inner ear and in CNS neurons

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2004.08.018 ◽

2005 ◽

Vol 28 (1) ◽

pp. 106-117 ◽

Cited By ~ 7

Author(s):

Ellen Reisinger ◽

Ulrike Zimmermann ◽

Marlies Knipper ◽

Jost Ludwig ◽

Nikolaj Klöcker ◽

...

Keyword(s):

Inner Ear ◽

Hair Cells ◽

Synaptic Protein ◽

Sensory Hair ◽

Sensory Hair Cells ◽

Cns Neurons

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Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1708894114 ◽

2017 ◽

Vol 114 (36) ◽

pp. 9695-9700 ◽

Cited By ~ 40

Author(s):

Alice Emptoz ◽

Vincent Michel ◽

Andrea Lelli ◽

Omar Akil ◽

Jacques Boutet de Monvel ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Inner Ear ◽

Usher Syndrome ◽

Vestibular Function ◽

Gene Replacement ◽

Syndrome Type ◽

Mechanoelectrical Transduction ◽

Efficient Gene ◽

Usher Syndrome Type

Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensitivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected.

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