Mouse Models of Human Pathogenic Variants of <i>TBC1D24</i> Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness
Human pathogenic variants of <i>TBC1D24</i> are associated with clinically heterogeneous phenotypes, including recessive nonsyndromic deafness DFNB86, dominant nonsyndromic deafness DFNA65, seizure accompanied by deafness, a variety of isolated seizure phenotypes and DOORS syndrome, char...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-09-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/11/10/1122 |
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doaj-31ff39366c4c451ebfd6ddc37e77d712 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Risa Tona Ivan A. Lopez Cristina Fenollar-Ferrer Rabia Faridi Claudio Anselmi Asma A. Khan Mohsin Shahzad Robert J. Morell Shoujun Gu Michael Hoa Lijin Dong Akira Ishiyama Inna A. Belyantseva Sheikh Riazuddin Thomas B. Friedman |
| spellingShingle |
Risa Tona Ivan A. Lopez Cristina Fenollar-Ferrer Rabia Faridi Claudio Anselmi Asma A. Khan Mohsin Shahzad Robert J. Morell Shoujun Gu Michael Hoa Lijin Dong Akira Ishiyama Inna A. Belyantseva Sheikh Riazuddin Thomas B. Friedman Mouse Models of Human Pathogenic Variants of <i>TBC1D24</i> Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness Genes <i>Tbc1d24</i> mouse models hearing loss DFNB86 DFNA65 DOORS syndromic deafness |
| author_facet |
Risa Tona Ivan A. Lopez Cristina Fenollar-Ferrer Rabia Faridi Claudio Anselmi Asma A. Khan Mohsin Shahzad Robert J. Morell Shoujun Gu Michael Hoa Lijin Dong Akira Ishiyama Inna A. Belyantseva Sheikh Riazuddin Thomas B. Friedman |
| author_sort |
Risa Tona |
| title |
Mouse Models of Human Pathogenic Variants of <i>TBC1D24</i> Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness |
| title_short |
Mouse Models of Human Pathogenic Variants of <i>TBC1D24</i> Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness |
| title_full |
Mouse Models of Human Pathogenic Variants of <i>TBC1D24</i> Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness |
| title_fullStr |
Mouse Models of Human Pathogenic Variants of <i>TBC1D24</i> Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness |
| title_full_unstemmed |
Mouse Models of Human Pathogenic Variants of <i>TBC1D24</i> Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness |
| title_sort |
mouse models of human pathogenic variants of <i>tbc1d24</i> associated with non-syndromic deafness dfnb86 and dfna65 and syndromes involving deafness |
| publisher |
MDPI AG |
| series |
Genes |
| issn |
2073-4425 |
| publishDate |
2020-09-01 |
| description |
Human pathogenic variants of <i>TBC1D24</i> are associated with clinically heterogeneous phenotypes, including recessive nonsyndromic deafness DFNB86, dominant nonsyndromic deafness DFNA65, seizure accompanied by deafness, a variety of isolated seizure phenotypes and DOORS syndrome, characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability and seizures. Thirty-five pathogenic variants of human <i>TBC1D24</i> associated with deafness have been reported. However, functions of TBC1D24 in the inner ear and the pathophysiology of TBC1D24-related deafness are unknown. In this study, a novel splice-site variant of <i>TBC1D24</i> c.965 + 1G > A in compound heterozygosity with c.641G > A p.(Arg214His) was found to be segregating in a Pakistani family. Affected individuals exhibited, either a deafness-seizure syndrome or nonsyndromic deafness. In human temporal bones, TBC1D24 immunolocalized in hair cells and spiral ganglion neurons, whereas in mouse cochlea, <i>Tbc1d24</i> expression was detected only in spiral ganglion neurons. We engineered mouse models of <i>DFNB86</i> p.(Asp70Tyr) and <i>DFNA65</i> p.(Ser178Leu) nonsyndromic deafness and syndromic forms of deafness p.(His336Glnfs*12) that have the same pathogenic variants that were reported for human <i>TBC1D24</i>. Unexpectedly, no auditory dysfunction was detected in <i>Tbc1d24</i> mutant mice, although homozygosity for some of the variants caused seizures or lethality. We provide some insightful supporting data to explain the phenotypic differences resulting from equivalent pathogenic variants of mouse <i>Tbc1d24</i> and human <i>TBC1D24</i>. |
| topic |
<i>Tbc1d24</i> mouse models hearing loss DFNB86 DFNA65 DOORS syndromic deafness |
| url |
https://www.mdpi.com/2073-4425/11/10/1122 |
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doaj-31ff39366c4c451ebfd6ddc37e77d7122020-11-25T03:47:00ZengMDPI AGGenes2073-44252020-09-01111122112210.3390/genes11101122Mouse Models of Human Pathogenic Variants of <i>TBC1D24</i> Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving DeafnessRisa Tona0Ivan A. Lopez1Cristina Fenollar-Ferrer2Rabia Faridi3Claudio Anselmi4Asma A. Khan5Mohsin Shahzad6Robert J. Morell7Shoujun Gu8Michael Hoa9Lijin Dong10Akira Ishiyama11Inna A. Belyantseva12Sheikh Riazuddin13Thomas B. Friedman14Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, Porter Neuroscience Research Center, National Institutes of Health, Bethesda, MD 20892, USAThe NIDCD National Temporal Laboratory at UCLA, Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USALaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, Porter Neuroscience Research Center, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, Porter Neuroscience Research Center, National Institutes of Health, Bethesda, MD 20892, USAResearch Center for Genetic Medicine, Children’s National Hospital, Washington, DC 20010, USANational Centre of Excellence in Molecular Biology, University of the Punjab Lahore, Lahore 53700, PakistanDepartment of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44080, PakistanGenomics and Computational Biology Core, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USAAuditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USAAuditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USAGenetic Engineering Core, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USAThe NIDCD National Temporal Laboratory at UCLA, Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USALaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, Porter Neuroscience Research Center, National Institutes of Health, Bethesda, MD 20892, USADepartment of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44080, PakistanLaboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, Porter Neuroscience Research Center, National Institutes of Health, Bethesda, MD 20892, USAHuman pathogenic variants of <i>TBC1D24</i> are associated with clinically heterogeneous phenotypes, including recessive nonsyndromic deafness DFNB86, dominant nonsyndromic deafness DFNA65, seizure accompanied by deafness, a variety of isolated seizure phenotypes and DOORS syndrome, characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability and seizures. Thirty-five pathogenic variants of human <i>TBC1D24</i> associated with deafness have been reported. However, functions of TBC1D24 in the inner ear and the pathophysiology of TBC1D24-related deafness are unknown. In this study, a novel splice-site variant of <i>TBC1D24</i> c.965 + 1G > A in compound heterozygosity with c.641G > A p.(Arg214His) was found to be segregating in a Pakistani family. Affected individuals exhibited, either a deafness-seizure syndrome or nonsyndromic deafness. In human temporal bones, TBC1D24 immunolocalized in hair cells and spiral ganglion neurons, whereas in mouse cochlea, <i>Tbc1d24</i> expression was detected only in spiral ganglion neurons. We engineered mouse models of <i>DFNB86</i> p.(Asp70Tyr) and <i>DFNA65</i> p.(Ser178Leu) nonsyndromic deafness and syndromic forms of deafness p.(His336Glnfs*12) that have the same pathogenic variants that were reported for human <i>TBC1D24</i>. Unexpectedly, no auditory dysfunction was detected in <i>Tbc1d24</i> mutant mice, although homozygosity for some of the variants caused seizures or lethality. We provide some insightful supporting data to explain the phenotypic differences resulting from equivalent pathogenic variants of mouse <i>Tbc1d24</i> and human <i>TBC1D24</i>.https://www.mdpi.com/2073-4425/11/10/1122<i>Tbc1d24</i> mouse modelshearing lossDFNB86DFNA65DOORSsyndromic deafness |