TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss

Abstract Several TBC1D24 variants are causally involved in the development of profound, prelingual hearing loss (HL) and different epilepsy syndromes inherited in an autosomal recessive manner. Only two TBC1D24 pathogenic variants have been linked with postlingual progressive autosomal dominant HL (...

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Autores principales:	Dominika Oziębło, Marcin L. Leja, Michal Lazniewski, Anna Sarosiak, Grażyna Tacikowska, Krzysztof Kochanek, Dariusz Plewczynski, Henryk Skarżyński, Monika Ołdak
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d17fac3e3c4a4413a34c33aa3fb78490
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spelling	oai:doaj.org-article:d17fac3e3c4a4413a34c33aa3fb784902021-12-02T16:50:22ZTBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss10.1038/s41598-021-89645-y2045-2322https://doaj.org/article/d17fac3e3c4a4413a34c33aa3fb784902021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89645-yhttps://doaj.org/toc/2045-2322Abstract Several TBC1D24 variants are causally involved in the development of profound, prelingual hearing loss (HL) and different epilepsy syndromes inherited in an autosomal recessive manner. Only two TBC1D24 pathogenic variants have been linked with postlingual progressive autosomal dominant HL (ADHL). To determine the role of TBC1D24 in the development of ADHL and to characterize the TBC1D24-related ADHL, clinical exome sequencing or targeted multigene (n = 237) panel were performed for probands (n = 102) from multigenerational ADHL families. In four families, TBC1D24-related HL was found based on the identification of three novel, likely pathogenic (c.553G>A, p.Asp185Asn; c.1460A>T, p. His487Leu or c.1461C>G, p.His487Gln) and one known (c.533C>T, p.Ser178Leu) TBC1D24 variant. Functional consequences of these variants were characterized by analyzing the proposed homology models of the human TBC1D24 protein. Variants not only in the TBC (p.Ser178Leu, p.Asp185Asn) but also in the TLDc domain (p.His487Gln, p.His487Leu) are involved in ADHL development, the latter two mutations probably affecting interactions between the domains. Clinically, progressive HL involving mainly mid and high frequencies was observed in the patients (n = 29). The progression of HL was calculated by constructing age-related typical audiograms. TBC1D24-related ADHL originates from the cochlear component of the auditory system, becomes apparent usually in the second decade of life and accounts for approximately 4% of ADHL cases. Given the high genetic heterogeneity of ADHL, TBC1D24 emerges as an important contributor to this type of HL.Dominika OziębłoMarcin L. LejaMichal LazniewskiAnna SarosiakGrażyna TacikowskaKrzysztof KochanekDariusz PlewczynskiHenryk SkarżyńskiMonika OłdakNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dominika Oziębło Marcin L. Leja Michal Lazniewski Anna Sarosiak Grażyna Tacikowska Krzysztof Kochanek Dariusz Plewczynski Henryk Skarżyński Monika Ołdak TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss
description	Abstract Several TBC1D24 variants are causally involved in the development of profound, prelingual hearing loss (HL) and different epilepsy syndromes inherited in an autosomal recessive manner. Only two TBC1D24 pathogenic variants have been linked with postlingual progressive autosomal dominant HL (ADHL). To determine the role of TBC1D24 in the development of ADHL and to characterize the TBC1D24-related ADHL, clinical exome sequencing or targeted multigene (n = 237) panel were performed for probands (n = 102) from multigenerational ADHL families. In four families, TBC1D24-related HL was found based on the identification of three novel, likely pathogenic (c.553G>A, p.Asp185Asn; c.1460A>T, p. His487Leu or c.1461C>G, p.His487Gln) and one known (c.533C>T, p.Ser178Leu) TBC1D24 variant. Functional consequences of these variants were characterized by analyzing the proposed homology models of the human TBC1D24 protein. Variants not only in the TBC (p.Ser178Leu, p.Asp185Asn) but also in the TLDc domain (p.His487Gln, p.His487Leu) are involved in ADHL development, the latter two mutations probably affecting interactions between the domains. Clinically, progressive HL involving mainly mid and high frequencies was observed in the patients (n = 29). The progression of HL was calculated by constructing age-related typical audiograms. TBC1D24-related ADHL originates from the cochlear component of the auditory system, becomes apparent usually in the second decade of life and accounts for approximately 4% of ADHL cases. Given the high genetic heterogeneity of ADHL, TBC1D24 emerges as an important contributor to this type of HL.
format	article
author	Dominika Oziębło Marcin L. Leja Michal Lazniewski Anna Sarosiak Grażyna Tacikowska Krzysztof Kochanek Dariusz Plewczynski Henryk Skarżyński Monika Ołdak
author_facet	Dominika Oziębło Marcin L. Leja Michal Lazniewski Anna Sarosiak Grażyna Tacikowska Krzysztof Kochanek Dariusz Plewczynski Henryk Skarżyński Monika Ołdak
author_sort	Dominika Oziębło
title	TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss
title_short	TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss
title_full	TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss
title_fullStr	TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss
title_full_unstemmed	TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss
title_sort	tbc1d24 emerges as an important contributor to progressive postlingual dominant hearing loss
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d17fac3e3c4a4413a34c33aa3fb78490
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TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss

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