Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 607557

SOLUTE CARRIER FAMILY 17 (VESICULAR GLUTAMATE COTRANSPORTER), MEMBER 8; SLC17A8

Alternative titles; symbols

SOLUTE CARRIER FAMILY 17 (SODIUM-DEPENDENT PHOSPHATE COTRANSPORTER), MEMBER 8

VESICULAR GLUTAMATE TRANSPORTER 3; VGLUT3

HGNC Approved Gene Symbol: SLC17A8

Cytogenetic location: 12q23.1 Genomic coordinates (GRCh38) : 12:100,357,074-100,422,055 (from NCBI)

Gene-Phenotype Relationships

TEXT

Cloning and Expression

By searching for homologs of VGLUT1 (SLC17A7; 605208) and VGLUT2 (SLC17A6; 607563), Takamori et al. (2002) identified a genomic sequence containing VGLUT3. Using a combination of PCR and 3-prime RACE, they cloned full-length VGLUT3 from a fetal brain cDNA library. The deduced 589-amino acid protein has a calculated molecular mass of about 65 kD. VGLUT3 contains 8 membrane-spanning segments and a long C terminus, similar to SLC17A7 and SLC17A6, with which it shares 72.5% and 72% amino acid identity, respectively. Northern blot analysis revealed a transcript of about 3.9 kb expressed in several brain regions, with highest expression in amygdala, medulla, and spinal cord. Weaker expression was detected in hippocampus, thalamus, and cerebellum, and no expression was detected in several other brain regions.

Gene Function

By expression of VGLUT3 in a human neuroendocrine cell line, Takamori et al. (2002) demonstrated ATP-dependent uptake of radiolabeled glutamate in light membrane vesicles. Disruption of the proton gradient by a proton ionophore or direct inhibition of V-ATPase (see 607027) reduced glutamate accumulation. Further characterization indicated that both the membrane electrical potential and the pH gradient associated with the proton gradient were required for full activity. VGLUT3 preferred glutamate over aspartate as substrate.

Seal et al. (2008) showed that in the cochlea, VGLUT3 accumulates glutamate in the synaptic vesicles of the sensory inner hair cells (IHCs) before releasing it into receptors of auditory nerve terminals.

Gene Structure

Takamori et al. (2002) determined that the VGLUT3 gene contains 12 exons and spans about 80 kb.

Mapping

By genomic sequence analysis, Takamori et al. (2002) mapped the VGLUT3 gene to chromosome 12.

Molecular Genetics

In 2 families segregating autosomal dominant deafness (DFNA25; 605583), including a family of Czech descent originally reported by Greene et al. (2001) and a family of German descent, Ruel et al. (2008) identified a heterozygous missense mutation (A211V; 607557.0001) in the SLC17A8 gene that was not present in 267 controls.

In a 47-year-old Korean man (family SD-38) with DFNA25, Ryu et al. (2016) identified heterozygosity for a frameshift mutation (c.616dupA; 605583.0002) in the SLC17A8 gene. The patient had bilateral severe sensorineural hearing loss. Other family members were said to be affected, but no other DNA studies were performed.

Animal Model

Seal et al. (2008) generated Slc17a8-null mice by homologous recombination in mouse embryonic stem cells. Mice lacking Vglut3 are profoundly deaf due to the absence of glutamate release from hair cells at the first synapse of the auditory pathway. The early degeneration of some cochlear ganglion neurons in knockout mice indicated an important developmental role for the glutamate released by hair cells before the onset of hearing.

Ruel et al. (2008) reported that Slc17a8-null mice lacked auditory nerve responses to acoustic stimuli, although auditory brainstem responses could be elicited by electrical stimuli, and robust otoacoustic emissions were recorded. Calcium ion-triggered synaptic vesicle turnover was normal in the inner hair cells of Slc17a8-null mice when probed by membrane capacitance measurements. Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent endings below sensory inner hair cells declined. Ribbon synapses remaining by 3 months of age had a normal ultrastructural appearance. Ruel et al. (2008) concluded 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 inner hair cell synapse.

Seal et al. (2009) reported that a small subset of cells in the dorsal root ganglion expresses the low abundance vesicular glutamate transporter VGLUT3. In the dorsal horn of the spinal cord, these afferents project to lamina I and the innermost layer of lamina II, which has been implicated in persistent pain caused by injury (see Malmberg et al., 1997). Because the different VGLUT isoforms generally have a nonredundant pattern of expression, Seal et al. (2009) used Vglut3 knockout mice to assess the role of VGLUT3+ primary afferents in the behavioral response to somatosensory input. The loss of Vglut3 specifically impairs mechanical pain sensation, and in particular the mechanical hypersensitivity to normally innocuous stimuli that accompanies inflammation, nerve injury, and trauma. Direct recording from Vglut3+ neurons in the dorsal root ganglion further identified them as a poorly understood population of unmyelinated, low threshold mechanoreceptors (C-LTMRs). Seal et al. (2009) concluded that their analysis of Vglut3-null mice indicated a critical role for C-LTMRs in the mechanical hypersensitivity caused by injury.

ALLELIC VARIANTS 2 Selected Examples):

.0001 DEAFNESS, AUTOSOMAL DOMINANT 25

SLC17A8, ALA211VAL
SNP: rs121918339, ClinVar: RCV000003256, RCV000724921

In 2 families segregating autosomal dominant deafness (DFNA25; 605583), including a family of Czech descent originally reported by Greene et al. (2001) and a family of German descent, Ruel et al. (2008) identified a c.632C-T transition in exon 5 of the SLC17A8 gene, resulting in an ala211-to-val (A211V) substitution. This mutation was not identified in 267 controls. The alanine at codon 211 is conserved in VGLUT3 across species and in all human VGLUT subtypes.

.0002 DEAFNESS, AUTOSOMAL DOMINANT 25

SLC17A8, 1-BP DUP, 616A
SNP: rs2135999616, ClinVar: RCV001391305

In a 47-year-old Korean man (family SD-38) with autosomal dominant deafness (DFNA25; 605583), Ryu et al. (2016) identified heterozygosity for a 1-bp duplication (c.616dupA) in the SLC17A8 gene, predicted to result in a frameshift and premature termination (Met206AsnfsTer4) with a protein lacking transmembrane domains 5-12. The mutation was identified by direct sequencing of the SLC17A8 gene. Other family members were said to be affected, but no other DNA studies were performed. The variant was not present in the 1000 Genomes Project or dbSNP databases or in 100 controls. Functional studies were not performed.

REFERENCES

1. Greene, C. C., McMillan, P. M., Barker, S. E., Kurnool, P., Lomax, M. I., Burmeister, M., Lesperance, M. M.DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24. Am. J. Hum. Genet. 68: 254-260, 2001. [PubMed: 11115382] [Full Text: https://doi.org/10.1086/316925\]
2. Malmberg, A. B., Chen, C., Tonegawa, S., Basbaum, A. I.Preserved acute pain and reduced neuropathic pain in mice lacking PKC-gamma. Science 278: 279-283, 1997. [PubMed: 9323205] [Full Text: https://doi.org/10.1126/science.278.5336.279\]
3. Ruel, J., Emery, S., Nouvian, R., Bersot, T., Amilhon, B., Van Rybroek, J. M., Rebillard, G., Lenoir, M., Eybalin, M., Delprat, B., Sivakumaran, T. A., Giros, B., El Mestikawy, S., Moser, T., Smith, R. J. H., Lesperance, M. M., Puel, J.-L.Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. Am. J. Hum. Genet. 83: 278-292, 2008. [PubMed: 18674745] [Full Text: https://doi.org/10.1016/j.ajhg.2008.07.008\]
4. Ryu, N., Sagong, B., Park, H.-J., Kim, M.-A., Lee, K.-Y., Choi, J. Y., Kim, U.-K.Screening of the SLC17A8 gene as a causative factor for autosomal dominant non-syndromic hearing loss in Koreans. BMC Med. Genet. 17: 6, 2016. [PubMed: 26797701] [Full Text: https://doi.org/10.1186/s12881-016-0269-3\]
5. Seal, R. P., Akil, O., Yi, E., Weber, C. M., Grant, L., Yoo, J., Clause, A., Kandler, K., Noebels, J. L., Glowatzki, E., Lustig, L. R., Edwards, R. H.Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3. Neuron 57: 263-275, 2008. [PubMed: 18215623] [Full Text: https://doi.org/10.1016/j.neuron.2007.11.032\]
6. Seal, R. P., Wang, X., Guan, Y., Raja, S. N., Woodbury, C. J., Basbaum, A. I., Edwards, R. H.Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 462: 651-655, 2009. [PubMed: 19915548] [Full Text: https://doi.org/10.1038/nature08505\]
7. Takamori, S., Malherbe, P., Broger, C., Jahn, R.Molecular cloning and functional characterization of human vesicular glutamate transporter 3. EMBO Rep. 3: 798-803, 2002. [PubMed: 12151341] [Full Text: https://doi.org/10.1093/embo-reports/kvf159\]

Contributors:

Hilary J. Vernon - updated : 05/11/2021
Ada Hamosh - updated : 1/6/2010
Patricia A. Hartz - updated : 9/22/2008

Creation Date:

Patricia A. Hartz : 2/11/2003

Edit History:

carol : 05/13/2021
carol : 05/12/2021
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carol : 10/27/2014
alopez : 1/15/2010
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terry : 12/2/2008
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