#605583
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-25 (DFNA25) is caused by heterozygous mutation in the SLC17A8 (607557) gene on chromosome 12q23.
Greene et al. (2001) reported a large Czech family in which several members had a nonsyndromic, slowly progressive hearing impairment. The frequencies most commonly affected were over 2,000 Hz. Age at onset varied from before age 20 to the sixth decade.
In a follow-up on the Czech family reported by Greene et al. (2001), Thirlwall et al. (2003) stated that 155 members over 4 generations had been examined. Affected family members typically had high frequency, slowly progressive sensorineural hearing loss with postlingual onset. All of those considered to be affected shared a common haplotype inherited from their mothers. Six unaffected family members had inherited the common haplotype from their fathers. Three male family members with significant hearing loss who did not share the common haplotype were considered to have a phenocopy because they had experienced significant occupational noise exposure.
The transmission pattern of DFNA25 in the families reported by Ruel et al. (2008) was consistent with autosomal dominant inheritance.
Using linkage analysis in a large multigenerational U.S. family of Czech descent, Greene et al. (2001) identified a novel locus, DFNA25, for dominant nonsyndromic hereditary hearing impairment. Based on recombinations in affected individuals, they localized DFNA25 to a 20-cM region of 12q21-q24, with a maximum 2-point lod score of 6.82 at recombination fraction 0.041 for D12S1030. Because the deafness in this family was delayed in onset, progressive, and involved loss of high frequencies, the phenotype was similar to presbycusis. For this reason, Greene et al. (2001) suggested that the DFNA25 locus might be a candidate region for presbycusis in the general population.
In a 6-year-old boy with congenital severe hearing loss, developmental delay, and minor anomalies, Petek et al. (2003) identified a de novo deletion in the 12q22-q24.1 region. By FISH analysis, they narrowed the DFNA25 critical region to a 13-cM interval and demonstrated that the derivative chromosome in this boy was paternal in origin.
In the original family studied by Greene et al. (2001) and in an American family of German descent, Ruel et al. (2008) identified a heterozygous ala211-to-val (A211V) missense mutation in the SLC17A8 gene (607557.0001) segregating with autosomal dominant deafness. The mutation was not present in 267 controls. Linkage disequilibrium analysis suggested that the families had a distant common ancestor. The alanine at position 211 is conserved in vesicular glutamate transporter-3, encoded by SLC17A8, across all species and in all human VGLUT subtypes, suggesting an important functional role.
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.
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) found 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.
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, images, related citations] [Full Text]
Petek, E., Windpassinger, C., Mach, M., Rauter, L., Scherer, S. W., Wagner, K., Kroisel, P. M. Molecular characterization of a 12q22-q24 deletion associated with congenital deafness: confirmation and refinement of the DFNA25 locus. Am. J. Med. Genet. 117A: 122-126, 2003. [PubMed: 12567408, related citations] [Full Text]
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, images, related citations] [Full Text]
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, images, related citations] [Full Text]
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, images, related citations] [Full Text]
Thirlwall, A. S., Brown, D. J., McMillan, P. M., Barker, S. E., Lesperance, M. M. Phenotypic characterization of hereditary hearing impairment linked to DFNA25. Arch. Otolaryng. Head Neck Surg. 129: 830-835, 2003. [PubMed: 12925340, related citations] [Full Text]
ORPHA: 90635; DO: 0110555;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q23.1 | Deafness, autosomal dominant 25 | 605583 | Autosomal dominant | 3 | SLC17A8 | 607557 |
A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-25 (DFNA25) is caused by heterozygous mutation in the SLC17A8 (607557) gene on chromosome 12q23.
Greene et al. (2001) reported a large Czech family in which several members had a nonsyndromic, slowly progressive hearing impairment. The frequencies most commonly affected were over 2,000 Hz. Age at onset varied from before age 20 to the sixth decade.
In a follow-up on the Czech family reported by Greene et al. (2001), Thirlwall et al. (2003) stated that 155 members over 4 generations had been examined. Affected family members typically had high frequency, slowly progressive sensorineural hearing loss with postlingual onset. All of those considered to be affected shared a common haplotype inherited from their mothers. Six unaffected family members had inherited the common haplotype from their fathers. Three male family members with significant hearing loss who did not share the common haplotype were considered to have a phenocopy because they had experienced significant occupational noise exposure.
The transmission pattern of DFNA25 in the families reported by Ruel et al. (2008) was consistent with autosomal dominant inheritance.
Using linkage analysis in a large multigenerational U.S. family of Czech descent, Greene et al. (2001) identified a novel locus, DFNA25, for dominant nonsyndromic hereditary hearing impairment. Based on recombinations in affected individuals, they localized DFNA25 to a 20-cM region of 12q21-q24, with a maximum 2-point lod score of 6.82 at recombination fraction 0.041 for D12S1030. Because the deafness in this family was delayed in onset, progressive, and involved loss of high frequencies, the phenotype was similar to presbycusis. For this reason, Greene et al. (2001) suggested that the DFNA25 locus might be a candidate region for presbycusis in the general population.
In a 6-year-old boy with congenital severe hearing loss, developmental delay, and minor anomalies, Petek et al. (2003) identified a de novo deletion in the 12q22-q24.1 region. By FISH analysis, they narrowed the DFNA25 critical region to a 13-cM interval and demonstrated that the derivative chromosome in this boy was paternal in origin.
In the original family studied by Greene et al. (2001) and in an American family of German descent, Ruel et al. (2008) identified a heterozygous ala211-to-val (A211V) missense mutation in the SLC17A8 gene (607557.0001) segregating with autosomal dominant deafness. The mutation was not present in 267 controls. Linkage disequilibrium analysis suggested that the families had a distant common ancestor. The alanine at position 211 is conserved in vesicular glutamate transporter-3, encoded by SLC17A8, across all species and in all human VGLUT subtypes, suggesting an important functional role.
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.
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) found 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.
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]
Petek, E., Windpassinger, C., Mach, M., Rauter, L., Scherer, S. W., Wagner, K., Kroisel, P. M. Molecular characterization of a 12q22-q24 deletion associated with congenital deafness: confirmation and refinement of the DFNA25 locus. Am. J. Med. Genet. 117A: 122-126, 2003. [PubMed: 12567408] [Full Text: https://doi.org/10.1002/ajmg.a.10155]
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]
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]
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]
Thirlwall, A. S., Brown, D. J., McMillan, P. M., Barker, S. E., Lesperance, M. M. Phenotypic characterization of hereditary hearing impairment linked to DFNA25. Arch. Otolaryng. Head Neck Surg. 129: 830-835, 2003. [PubMed: 12925340] [Full Text: https://doi.org/10.1001/archotol.129.8.830]
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