Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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
_version_ 1783602693498994688
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
work_keys_str_mv AT tonarisa mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT lopezivana mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT fenollarferrercristina mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT faridirabia mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT anselmiclaudio mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT khanasmaa mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT shahzadmohsin mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT morellrobertj mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT gushoujun mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT hoamichael mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT donglijin mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT ishiyamaakira mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT belyantsevainnaa mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT riazuddinsheikh mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness
AT friedmanthomasb mousemodelsofhumanpathogenicvariantsoftbc1d24associatedwithnonsyndromicdeafnessdfnb86anddfna65andsyndromesinvolvingdeafness