#614617
Table of Contents
A number sign (#) is used with this entry because autosomal recessive deafness-86 (DFNB86) is caused by homozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13.
Heterozygous mutation in the TBC1D24 gene results in autosomal dominant deafness-65 (DFNA65; 616044), which shows later onset than DFNB86.
Ali et al. (2012) reported a consanguineous Pakistani family in which 11 individuals had prelingual onset of profound hearing loss affecting all frequencies. There were no additional features or history of vestibular difficulties, but sophisticated testing of vestibular function was not performed.
The transmission pattern of deafness in the consanguineous Pakistani family reported by Ali et al. (2012) was consistent with autosomal recessive inheritance.
By genomewide linkage analysis of a consanguineous Pakistani family with prelingual onset of profound hearing loss, Ali et al. (2012) identified a locus, termed DFNB86, on chromosome 16p13.3 (maximum 2-point lod score of 8.54 at D16S3024). Haplotype analysis delineated a 3.09-Mb candidate region between the telomere of 16p and D16S3070. By assuming homozygosity for the putative mutation, the candidate region could be reduced to a 1.44-Mb interval between D16S3024 and D16S3070. Sequencing of 6 candidate genes in this interval did not reveal any pathogenic mutations.
In affected members of 4 consanguineous Pakistani families with autosomal recessive deafness-86, including the family reported by Ali et al. (2012), Rehman et al. (2014) identified 2 different homozygous missense mutations in the TBC1D24 gene (D70Y, 613577.0012 and R293P, 613577.0013). The mutations were found using a combination of linkage analysis and whole-exome sequencing. Functional studies of the variants were not performed. Detailed analysis of 2 of the families revealed that seizures did not segregate with deafness; only 1 deaf patient among both families had childhood febrile seizures.
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 and DFNA65 (616044), 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.
Ali, R. A., Rehman, A. U., Khan, S. N., Husnain, T., Riazuddin, S., Friedman, T. B., Ahmed, Z. M., Riazuddin, S. DFNB86, a novel autosomal recessive non-syndromic deafness locus on chromosome 16p13.3. (Letter) Clin. Genet. 81: 498-500, 2012. [PubMed: 22211675, related citations] [Full Text]
Rehman, A. U., Santos-Cortez, R. L. P., Morell, R. J., Drummond, M. C., Ito, T., Lee, K., Khan, A. A., Basra, M. A. R., Wasif, N., Ayub, M., Ali, R. A., Raza, S. I., and 13 others. Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86. Am. J. Hum. Genet. 94: 144-152, 2014. [PubMed: 24387994, 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]
ORPHA: 90636; DO: 0110532;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
16p13.3 | Deafness, autosomal recessive 86 | 614617 | Autosomal recessive | 3 | TBC1D24 | 613577 |
A number sign (#) is used with this entry because autosomal recessive deafness-86 (DFNB86) is caused by homozygous mutation in the TBC1D24 gene (613577) on chromosome 16p13.
Heterozygous mutation in the TBC1D24 gene results in autosomal dominant deafness-65 (DFNA65; 616044), which shows later onset than DFNB86.
Ali et al. (2012) reported a consanguineous Pakistani family in which 11 individuals had prelingual onset of profound hearing loss affecting all frequencies. There were no additional features or history of vestibular difficulties, but sophisticated testing of vestibular function was not performed.
The transmission pattern of deafness in the consanguineous Pakistani family reported by Ali et al. (2012) was consistent with autosomal recessive inheritance.
By genomewide linkage analysis of a consanguineous Pakistani family with prelingual onset of profound hearing loss, Ali et al. (2012) identified a locus, termed DFNB86, on chromosome 16p13.3 (maximum 2-point lod score of 8.54 at D16S3024). Haplotype analysis delineated a 3.09-Mb candidate region between the telomere of 16p and D16S3070. By assuming homozygosity for the putative mutation, the candidate region could be reduced to a 1.44-Mb interval between D16S3024 and D16S3070. Sequencing of 6 candidate genes in this interval did not reveal any pathogenic mutations.
In affected members of 4 consanguineous Pakistani families with autosomal recessive deafness-86, including the family reported by Ali et al. (2012), Rehman et al. (2014) identified 2 different homozygous missense mutations in the TBC1D24 gene (D70Y, 613577.0012 and R293P, 613577.0013). The mutations were found using a combination of linkage analysis and whole-exome sequencing. Functional studies of the variants were not performed. Detailed analysis of 2 of the families revealed that seizures did not segregate with deafness; only 1 deaf patient among both families had childhood febrile seizures.
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 and DFNA65 (616044), 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.
Ali, R. A., Rehman, A. U., Khan, S. N., Husnain, T., Riazuddin, S., Friedman, T. B., Ahmed, Z. M., Riazuddin, S. DFNB86, a novel autosomal recessive non-syndromic deafness locus on chromosome 16p13.3. (Letter) Clin. Genet. 81: 498-500, 2012. [PubMed: 22211675] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01729.x]
Rehman, A. U., Santos-Cortez, R. L. P., Morell, R. J., Drummond, M. C., Ito, T., Lee, K., Khan, A. A., Basra, M. A. R., Wasif, N., Ayub, M., Ali, R. A., Raza, S. I., and 13 others. Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86. Am. J. Hum. Genet. 94: 144-152, 2014. [PubMed: 24387994] [Full Text: https://doi.org/10.1016/j.ajhg.2013.12.004]
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]
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