Journal article
Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice
American journal of human genetics, Vol.83(2), pp.278-292
08/2008
DOI: 10.1016/j.ajhg.2008.07.008
PMCID: PMC2495073
PMID: 18674745
Abstract
Autosomal-dominant sensorineural hearing loss is genetically heterogeneous, with a phenotype closely resembling presbycusis, the most common sensory defect associated with aging in humans. We have identified SLC17A8, which encodes the vesicular glutamate transporter-3 (VGLUT3), as the gene responsible for DFNA25, an autosomal-dominant form of progressive, high-frequency nonsyndromic deafness. In two unrelated families, a heterozygous missense mutation, c.632C-->T (p.A211V), was found to segregate with DFNA25 deafness and was not present in 267 controls. Linkage-disequilibrium analysis suggested that the families have a distant common ancestor. The A211 residue is conserved in VGLUT3 across species and in all human VGLUT subtypes (VGLUT1-3), suggesting an important functional role. In the cochlea, VGLUT3 accumulates glutamate in the synaptic vesicles of the sensory inner hair cells (IHCs) before releasing it onto receptors of auditory-nerve terminals. Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to acoustic stimuli, although auditory brainstem responses could be elicited by electrical stimuli, and robust otoacoustic emissions were recorded. Ca(2+)-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice when probed by membrane capacitance measurements at 2 weeks of age. Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent endings below sensory IHCs declined. Ribbon synapses remaining by 3 months of age had a normal ultrastructural appearance. We conclude that deafness in Slc17a8-deficient mice is due to a specific defect of vesicular glutamate uptake and release and that VGLUT3 is essential for auditory coding at the IHC synapse.
Details
- Title: Subtitle
- Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice
- Creators
- Jérôme Ruel - Physiopathologie et thérapie des déficits sensoriels et moteursSarah Emery - Division of Pediatric OtolaryngologyRégis NouvianTiphaine Bersot - Physiopathologie et thérapie des déficits sensoriels et moteursBénédicte Amilhon - Neurobiologie et PsychiatrieJana Van Rybroek - Department of Otolaryngology and Head and Neck SurgeryGuy Rebillard - Physiopathologie et thérapie des déficits sensoriels et moteursMarc Lenoir - Physiopathologie et thérapie des déficits sensoriels et moteursMichel Eybalin - Physiopathologie et thérapie des déficits sensoriels et moteursBenjamin Delprat - Physiopathologie et thérapie des déficits sensoriels et moteursTheru Sivakumaran - Division of Pediatric OtolaryngologyBruno Giros - Neurobiologie et PsychiatrieSalah El Mestikawy - Neurobiologie et PsychiatrieTobias MoserRichard Smith - Department of Otolaryngology and Head and Neck SurgeryMarci Lesperance - Division of Pediatric OtolaryngologyJean-Luc Puel - Physiopathologie et thérapie des déficits sensoriels et moteurs
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.83(2), pp.278-292
- DOI
- 10.1016/j.ajhg.2008.07.008
- PMID
- 18674745
- PMCID
- PMC2495073
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- Elsevier (Cell Press)
- Language
- English
- Date published
- 08/2008
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984006424102771
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