Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice.
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.
Ruel
Jérôme
J
Inserm U 583, Institut des Neurosciences, Hôpital Saint Eloi, 34091 Montpellier, France; Université Montpellier 1, 34091 Montpellier, France.
Emery
Sarah
S
Nouvian
Régis
R
Bersot
Tiphaine
T
Amilhon
Bénédicte
B
Van Rybroek
Jana M
JM
Rebillard
Guy
G
Lenoir
Marc
M
Eybalin
Michel
M
Delprat
Benjamin
B
Sivakumaran
Theru A
TA
Giros
Bruno
B
El Mestikawy
Salah
S
Moser
Tobias
T
Smith
Richard J H
RJ
Lesperance
Marci M
MM
Puel
Jean-Luc
JL
D026922:Amino Acid Transport Systems, Acidic / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D002874:Chromosome Mapping; D003638:Deafness / Q000235:genetics*; D004195:Disease Models, Animal; D016678:Genome; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006801:Humans; D015810:Linkage Disequilibrium; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D050496:Vesicular Glutamate Transport Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology
D026922:Amino Acid Transport Systems, Acidic; D050496:Vesicular Glutamate Transport Proteins; C460879:SLC17A8 protein, human; C504941:Slc17a8 protein, mouse