Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice.

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.

• Authors: Jérôme Ruel, Sarah Emery, Régis Nouvian, Tiphaine Bersot, Bénédicte Amilhon, Jana M Van Rybroek, Guy Rebillard, Marc Lenoir, Michel Eybalin, Benjamin Delprat, Theru A Sivakumaran, Bruno Giros, Salah El Mestikawy, Tobias Moser, Richard J H Smith, Marci M Lesperance, Jean-Luc Puel
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 83 Issue 2 Pg. 278-92 (Aug 2008) ISSN: 1537-6605 [Electronic] United States
• PMID: 18674745 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Transport Systems, Acidic
• SLC17A8 protein, human
• Vesicular Glutamate Transport Proteins
• vesicular glutamate transporter 3, mouse

Topics

• Amino Acid Transport Systems, Acidic (genetics, metabolism, physiology)
• Animals
• Chromosome Mapping
• Deafness (genetics)
• Disease Models, Animal
• Genome
• Hair Cells, Auditory (metabolism)
• Humans
• Linkage Disequilibrium
• Mice
• Mice, Knockout
• Models, Genetic
• Mutation
• Polymorphism, Single Nucleotide
• Vesicular Glutamate Transport Proteins (genetics, metabolism, physiology)