A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study

Inherited hearing impairment is a remarkably heterogeneous monogenic condition, involving hundreds of genes, most of them with very small (< 1%) epidemiological contributions. The exception is GJB2, the gene encoding connexin-26 and underlying DFNB1, which is the most frequent type of autosomal r...

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Autores: Domínguez, María, Murillo-Cuesta, Silvia, Contreras, Julio, Cantero, Marta, Garrido, Gema, Martín-Bernardo, Belén, Gómez-Rosas, Belén, Fernández, Almudena, Castillo, Francisco J. del, Montoliu, Lluís, Varela-Nieto, Isabel, Castillo, Ignacio del
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/357153
Acesso em linha:http://hdl.handle.net/10261/357153
Access Level:acceso abierto
Palavra-chave:Inherited hearing impairment
DFNB1
GJB2
Connnexin-26
Murine models
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oai_identifier_str oai:digital.csic.es:10261/357153
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study
title A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study
spellingShingle A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study
Domínguez, María
Inherited hearing impairment
DFNB1
GJB2
Connnexin-26
Murine models
title_short A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study
title_full A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study
title_fullStr A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study
title_full_unstemmed A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study
title_sort A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study
dc.creator.none.fl_str_mv Domínguez, María
Murillo-Cuesta, Silvia
Contreras, Julio
Cantero, Marta
Garrido, Gema
Martín-Bernardo, Belén
Gómez-Rosas, Belén
Fernández, Almudena
Castillo, Francisco J. del
Montoliu, Lluís
Varela-Nieto, Isabel
Castillo, Ignacio del
author Domínguez, María
author_facet Domínguez, María
Murillo-Cuesta, Silvia
Contreras, Julio
Cantero, Marta
Garrido, Gema
Martín-Bernardo, Belén
Gómez-Rosas, Belén
Fernández, Almudena
Castillo, Francisco J. del
Montoliu, Lluís
Varela-Nieto, Isabel
Castillo, Ignacio del
author_role author
author2 Murillo-Cuesta, Silvia
Contreras, Julio
Cantero, Marta
Garrido, Gema
Martín-Bernardo, Belén
Gómez-Rosas, Belén
Fernández, Almudena
Castillo, Francisco J. del
Montoliu, Lluís
Varela-Nieto, Isabel
Castillo, Ignacio del
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Comunidad de Madrid
Ministerio de Economía y Competitividad (España)
Centro de Investigación Biomédica en Red Enfermedades Raras (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Inherited hearing impairment
DFNB1
GJB2
Connnexin-26
Murine models
topic Inherited hearing impairment
DFNB1
GJB2
Connnexin-26
Murine models
description Inherited hearing impairment is a remarkably heterogeneous monogenic condition, involving hundreds of genes, most of them with very small (< 1%) epidemiological contributions. The exception is GJB2, the gene encoding connexin-26 and underlying DFNB1, which is the most frequent type of autosomal recessive non-syndromic hearing impairment (ARNSHI) in most populations (up to 40% of ARNSHI cases). DFNB1 is caused by different types of pathogenic variants in GJB2, but also by large deletions that keep the gene intact but remove an upstream regulatory element that is essential for its expression. Such large deletions, found in most populations, behave as complete loss-of-function variants, usually associated with a profound hearing impairment. By using CRISPR-Cas9 genetic edition, we have generated a murine model (Dfnb1em274) that reproduces the most frequent of those deletions, del(GJB6-D13S1830). Dfnb1em274 homozygous mice are viable, bypassing the embryonic lethality of the Gjb2 knockout, and present a phenotype of profound hearing loss (> 90 dB SPL) that correlates with specific structural abnormalities in the cochlea. We show that Gjb2 expression is nearly abolished and its protein product, Cx26, is nearly absent all throughout the cochlea, unlike previous conditional knockouts in which Gjb2 ablation was not obtained in all cell types. The Dfnb1em274 model recapitulates the clinical presentation of patients harbouring the del(GJB6-D13S1830) variant and thus it is a valuable tool to study the pathological mechanisms of DFNB1 and to assay therapies for this most frequent type of human ARNSHI.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/357153
url http://hdl.handle.net/10261/357153
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
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info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115274RB-I00
IND2020/BMD-17454
P2022/BMD7236
info:eu-repo/grantAgreement/MINECO//BIO2015-70978-R
Domínguez, María; Murillo-Cuesta, Silvia; Contreras, Julio; Cantero, Marta; Garrido, Gema; Martín-Bernardo, Belén; Gómez-Rosas, Belén; Fernández, Almudena; Castillo, Francisco J. del; Montoliu, Lluís; Varela-Nieto, Isabel; Castillo, Ignacio del; 2024; Additional file 1 of A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26704938.v1
https://doi.org/10.1186/s12864-024-10289-z
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological studyDomínguez, MaríaMurillo-Cuesta, SilviaContreras, JulioCantero, MartaGarrido, GemaMartín-Bernardo, BelénGómez-Rosas, BelénFernández, AlmudenaCastillo, Francisco J. delMontoliu, LluísVarela-Nieto, IsabelCastillo, Ignacio delInherited hearing impairmentDFNB1GJB2Connnexin-26Murine modelsInherited hearing impairment is a remarkably heterogeneous monogenic condition, involving hundreds of genes, most of them with very small (< 1%) epidemiological contributions. The exception is GJB2, the gene encoding connexin-26 and underlying DFNB1, which is the most frequent type of autosomal recessive non-syndromic hearing impairment (ARNSHI) in most populations (up to 40% of ARNSHI cases). DFNB1 is caused by different types of pathogenic variants in GJB2, but also by large deletions that keep the gene intact but remove an upstream regulatory element that is essential for its expression. Such large deletions, found in most populations, behave as complete loss-of-function variants, usually associated with a profound hearing impairment. By using CRISPR-Cas9 genetic edition, we have generated a murine model (Dfnb1em274) that reproduces the most frequent of those deletions, del(GJB6-D13S1830). Dfnb1em274 homozygous mice are viable, bypassing the embryonic lethality of the Gjb2 knockout, and present a phenotype of profound hearing loss (> 90 dB SPL) that correlates with specific structural abnormalities in the cochlea. We show that Gjb2 expression is nearly abolished and its protein product, Cx26, is nearly absent all throughout the cochlea, unlike previous conditional knockouts in which Gjb2 ablation was not obtained in all cell types. The Dfnb1em274 model recapitulates the clinical presentation of patients harbouring the del(GJB6-D13S1830) variant and thus it is a valuable tool to study the pathological mechanisms of DFNB1 and to assay therapies for this most frequent type of human ARNSHI.This work was supported by the Instituto de Salud Carlos III (ISCIII), Madrid, Spain, National Plan for Scientific and Technical Research and Innovation 2017–2020, with cofunding from the European Regional Development Fund, “A way to make Europe”, grant number PI20/00619 (to I. d. C.); by MINECO/FEDER THERAPY PID2020-115274RB-I00/AEI/10.13039/501100011033, CM IND2020/BMD-17454 and MINA-CM P2022/BMD7236 (to IVN); and by MINECO BIO2015-70978-R and intramural funds from Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (to L.M.). SMC and BMB hold CIBERER-ISCIII contracts.Peer reviewedBioMed CentralInstituto de Salud Carlos IIIMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Comunidad de MadridMinisterio de Economía y Competitividad (España)Centro de Investigación Biomédica en Red Enfermedades Raras (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/357153reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115274RB-I00IND2020/BMD-17454P2022/BMD7236info:eu-repo/grantAgreement/MINECO//BIO2015-70978-RDomínguez, María; Murillo-Cuesta, Silvia; Contreras, Julio; Cantero, Marta; Garrido, Gema; Martín-Bernardo, Belén; Gómez-Rosas, Belén; Fernández, Almudena; Castillo, Francisco J. del; Montoliu, Lluís; Varela-Nieto, Isabel; Castillo, Ignacio del; 2024; Additional file 1 of A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.26704938.v1https://doi.org/10.1186/s12864-024-10289-zSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3571532026-05-22T06:33:51Z
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