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Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness
Human pathogenic variants of TBC1D24 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 deafne...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598720/ https://www.ncbi.nlm.nih.gov/pubmed/32987832 http://dx.doi.org/10.3390/genes11101122 |
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author | Tona, Risa Lopez, Ivan A. Fenollar-Ferrer, Cristina Faridi, Rabia Anselmi, Claudio Khan, Asma A. Shahzad, Mohsin Morell, Robert J. Gu, Shoujun Hoa, Michael Dong, Lijin Ishiyama, Akira Belyantseva, Inna A. Riazuddin, Sheikh Friedman, Thomas B. |
author_facet | Tona, Risa Lopez, Ivan A. Fenollar-Ferrer, Cristina Faridi, Rabia Anselmi, Claudio Khan, Asma A. Shahzad, Mohsin Morell, Robert J. Gu, Shoujun Hoa, Michael Dong, Lijin Ishiyama, Akira Belyantseva, Inna A. Riazuddin, Sheikh Friedman, Thomas B. |
author_sort | Tona, Risa |
collection | PubMed |
description | Human pathogenic variants of TBC1D24 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 TBC1D24 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 TBC1D24 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, Tbc1d24 expression was detected only in spiral ganglion neurons. We engineered mouse models of DFNB86 p.(Asp70Tyr) and DFNA65 p.(Ser178Leu) nonsyndromic deafness and syndromic forms of deafness p.(His336Glnfs*12) that have the same pathogenic variants that were reported for human TBC1D24. Unexpectedly, no auditory dysfunction was detected in Tbc1d24 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 Tbc1d24 and human TBC1D24. |
format | Online Article Text |
id | pubmed-7598720 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75987202020-10-31 Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness Tona, Risa Lopez, Ivan A. Fenollar-Ferrer, Cristina Faridi, Rabia Anselmi, Claudio Khan, Asma A. Shahzad, Mohsin Morell, Robert J. Gu, Shoujun Hoa, Michael Dong, Lijin Ishiyama, Akira Belyantseva, Inna A. Riazuddin, Sheikh Friedman, Thomas B. Genes (Basel) Article Human pathogenic variants of TBC1D24 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 TBC1D24 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 TBC1D24 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, Tbc1d24 expression was detected only in spiral ganglion neurons. We engineered mouse models of DFNB86 p.(Asp70Tyr) and DFNA65 p.(Ser178Leu) nonsyndromic deafness and syndromic forms of deafness p.(His336Glnfs*12) that have the same pathogenic variants that were reported for human TBC1D24. Unexpectedly, no auditory dysfunction was detected in Tbc1d24 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 Tbc1d24 and human TBC1D24. MDPI 2020-09-24 /pmc/articles/PMC7598720/ /pubmed/32987832 http://dx.doi.org/10.3390/genes11101122 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Tona, Risa Lopez, Ivan A. Fenollar-Ferrer, Cristina Faridi, Rabia Anselmi, Claudio Khan, Asma A. Shahzad, Mohsin Morell, Robert J. Gu, Shoujun Hoa, Michael Dong, Lijin Ishiyama, Akira Belyantseva, Inna A. Riazuddin, Sheikh Friedman, Thomas B. Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness |
title | Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness |
title_full | Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness |
title_fullStr | Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness |
title_full_unstemmed | Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness |
title_short | Mouse Models of Human Pathogenic Variants of TBC1D24 Associated with Non-Syndromic Deafness DFNB86 and DFNA65 and Syndromes Involving Deafness |
title_sort | mouse models of human pathogenic variants of tbc1d24 associated with non-syndromic deafness dfnb86 and dfna65 and syndromes involving deafness |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598720/ https://www.ncbi.nlm.nih.gov/pubmed/32987832 http://dx.doi.org/10.3390/genes11101122 |
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