#616044
Table of Contents
A number sign (#) is used with this entry because autosomal dominant deafness-65 (DFNA65) is caused by heterozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13.
Biallelic mutation in the TBC1D24 gene causes autosomal recessive deafness-86 (DFNB86; 614617).
Autosomal dominant deafness-65 is characterized by postlingual onset of slowly progressive hearing loss in the third decade. Initially affecting the high frequencies, the hearing loss eventually affects all frequencies and results in severe to profound deafness in the seventh decade. Vestibular function is normal (Zhang et al., 2014).
Zhang et al. (2014) reported a 4-generation Han Chinese family in which at least 11 members had onset of nonsyndromic hearing impairment before 40 years of age. Most affected individuals developed slowly progressive hearing impairment affecting high frequencies in their twenties. The deafness progressed to severe to profound hearing loss affecting all frequencies in the seventh decade. There was no evidence of vestibular dysfunction.
Azaiez et al. (2014) reported a multigenerational family of European descent with postlingual onset of progressive hearing loss beginning in the third decade. Audiograms of affected individuals had a gently downsloping configuration.
The transmission pattern of DFNA65 in the families reported by Zhang et al. (2014) was consistent with autosomal dominant inheritance.
By genomewide linkage analysis of a family with autosomal dominant postlingual onset of hearing loss, Zhang et al. (2014) found linkage to a 2.07-Mb interval on chromosome 16p13.3 (maximum lod score of 3.80 at marker rs7187438). This interval overlapped with that for DFNB86.
Simultaneously and independently, Zhang et al. (2014) and Azaiez et al. (2014) identified the same heterozygous missense mutation in the TBC1D24 gene (S178L; 613577.0014) in affected members of a Han Chinese family and a European family, respectively, with young adult-onset progressive hearing loss. The mutations, which were found using a combination of mapping and whole-exome sequencing, segregated with the disorder in each family. Functional studies were not performed; however, in the developing mouse cochlea, Tbc1d24 was found by both groups to be expressed in the stereocilia of inner and outer hair cells as well as in spiral ganglion neurons. Zhang et al. (2014) suggested that the mutation resulted in a gain of function or a dominant-negative effect.
Tona et al. (2020) generated mouse models for the human TBC1D24 mutations asp70 to tyr (D70Y; 613577.0012) and ser178 to leu (S178L; 613577.0014) associated with nonsyndromic deafness DFNB86 (614617) and DFNA65, respectively. Unlike their corresponding human phenotypes, mice with the D70Y or S178L mutation in Tbc1d24 did not have hearing loss. The authors also generated mice compound heterozygous for the Ser324ThrfsTer3 (613577.0004) and His336GlnfsTer12 (613577.0010) Tbc1d24 mutations as a model for human syndromic deafness and found that these mutant mice recapitulated the human seizure phenotype but had normal hearing. Modeling of mouse and human TBC1D24 suggested that deafness arising from the TBC1D24 D70Y mutation in human, but not in mouse, is related to evolutionary divergence in functional necessity and cell type-specific regulation of expression of human TBC1D24 compared with mouse Tbc1d24. In contrast, the S178L mutation had a stabilizing effect on the Tbc1d24 protein in mouse, but not in human, providing a possible explanation for the phenotypic differences in mice and humans with this TBC1D24 mutation.
Azaiez, H., Booth, K. T., Bu, F., Huygen, P., Shibata, S. B., Shearer, A. E., Kolbe, D., Meyer, N., Black-Ziegelbein, E. A., Smith, R. J. H. TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss. Hum. Mutat. 35: 819-823, 2014. [PubMed: 24729539, images, related citations] [Full Text]
Tona, R., Lopez, I. A., Fenollar-Ferrer, C., Faridi, R., Anselmi, C., Khan, A. A., Shahzad, M., Morell, R. J., Gu, S., Hoa, M., Dong, L., Ishiyama, A., Belyantseva, I. A., Riazuddin, S., Friedman, T. B. Mouse models of human pathogenic variants of TBC1D24 associated with non-syndromic deafness DFNB86 and DFNA65 and syndromes involving deafness. Genes 11: 1122, 2020. [PubMed: 32987832, images, related citations] [Full Text]
Zhang, L., Hu, L., Chai, Y., Pang, X., Yang, T., Wu, H. A dominant mutation in the stereocilia-expressing gene TBC1D24 is a probable cause for nonsyndromic hearing impairment. Hum. Mutat. 35: 814-818, 2014. [PubMed: 24729547, related citations] [Full Text]
ORPHA: 90635; DO: 0110586;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Deafness, autosomal dominant 65 | 616044 | Autosomal dominant | 3 | TBC1D24 | 613577 |
A number sign (#) is used with this entry because autosomal dominant deafness-65 (DFNA65) is caused by heterozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13.
Biallelic mutation in the TBC1D24 gene causes autosomal recessive deafness-86 (DFNB86; 614617).
Autosomal dominant deafness-65 is characterized by postlingual onset of slowly progressive hearing loss in the third decade. Initially affecting the high frequencies, the hearing loss eventually affects all frequencies and results in severe to profound deafness in the seventh decade. Vestibular function is normal (Zhang et al., 2014).
Zhang et al. (2014) reported a 4-generation Han Chinese family in which at least 11 members had onset of nonsyndromic hearing impairment before 40 years of age. Most affected individuals developed slowly progressive hearing impairment affecting high frequencies in their twenties. The deafness progressed to severe to profound hearing loss affecting all frequencies in the seventh decade. There was no evidence of vestibular dysfunction.
Azaiez et al. (2014) reported a multigenerational family of European descent with postlingual onset of progressive hearing loss beginning in the third decade. Audiograms of affected individuals had a gently downsloping configuration.
The transmission pattern of DFNA65 in the families reported by Zhang et al. (2014) was consistent with autosomal dominant inheritance.
By genomewide linkage analysis of a family with autosomal dominant postlingual onset of hearing loss, Zhang et al. (2014) found linkage to a 2.07-Mb interval on chromosome 16p13.3 (maximum lod score of 3.80 at marker rs7187438). This interval overlapped with that for DFNB86.
Simultaneously and independently, Zhang et al. (2014) and Azaiez et al. (2014) identified the same heterozygous missense mutation in the TBC1D24 gene (S178L; 613577.0014) in affected members of a Han Chinese family and a European family, respectively, with young adult-onset progressive hearing loss. The mutations, which were found using a combination of mapping and whole-exome sequencing, segregated with the disorder in each family. Functional studies were not performed; however, in the developing mouse cochlea, Tbc1d24 was found by both groups to be expressed in the stereocilia of inner and outer hair cells as well as in spiral ganglion neurons. Zhang et al. (2014) suggested that the mutation resulted in a gain of function or a dominant-negative effect.
Tona et al. (2020) generated mouse models for the human TBC1D24 mutations asp70 to tyr (D70Y; 613577.0012) and ser178 to leu (S178L; 613577.0014) associated with nonsyndromic deafness DFNB86 (614617) and DFNA65, respectively. Unlike their corresponding human phenotypes, mice with the D70Y or S178L mutation in Tbc1d24 did not have hearing loss. The authors also generated mice compound heterozygous for the Ser324ThrfsTer3 (613577.0004) and His336GlnfsTer12 (613577.0010) Tbc1d24 mutations as a model for human syndromic deafness and found that these mutant mice recapitulated the human seizure phenotype but had normal hearing. Modeling of mouse and human TBC1D24 suggested that deafness arising from the TBC1D24 D70Y mutation in human, but not in mouse, is related to evolutionary divergence in functional necessity and cell type-specific regulation of expression of human TBC1D24 compared with mouse Tbc1d24. In contrast, the S178L mutation had a stabilizing effect on the Tbc1d24 protein in mouse, but not in human, providing a possible explanation for the phenotypic differences in mice and humans with this TBC1D24 mutation.
Azaiez, H., Booth, K. T., Bu, F., Huygen, P., Shibata, S. B., Shearer, A. E., Kolbe, D., Meyer, N., Black-Ziegelbein, E. A., Smith, R. J. H. TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss. Hum. Mutat. 35: 819-823, 2014. [PubMed: 24729539] [Full Text: https://doi.org/10.1002/humu.22557]
Tona, R., Lopez, I. A., Fenollar-Ferrer, C., Faridi, R., Anselmi, C., Khan, A. A., Shahzad, M., Morell, R. J., Gu, S., Hoa, M., Dong, L., Ishiyama, A., Belyantseva, I. A., Riazuddin, S., Friedman, T. B. Mouse models of human pathogenic variants of TBC1D24 associated with non-syndromic deafness DFNB86 and DFNA65 and syndromes involving deafness. Genes 11: 1122, 2020. [PubMed: 32987832] [Full Text: https://doi.org/10.3390/genes11101122]
Zhang, L., Hu, L., Chai, Y., Pang, X., Yang, T., Wu, H. A dominant mutation in the stereocilia-expressing gene TBC1D24 is a probable cause for nonsyndromic hearing impairment. Hum. Mutat. 35: 814-818, 2014. [PubMed: 24729547] [Full Text: https://doi.org/10.1002/humu.22558]
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