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Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants

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Morín, Matias & Borreguero, Lucía &  Booth, Kevin T & Lachgar, María & Huygen, Patrick & Villamar, Manuela & Mayo, Fernando & Barrio, Luis Carlos & Santos Serrão de Castro, Luciana & Morales, Carmelo & del Castillo, Ignacio & Arellano, Beatriz & Tellería, Dolores & Smith, Richard J.H. & Azaiez, Hela & Moreno Pelayo, Miguel Angel (2020 ) .Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants.

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Morín, Matias & Borreguero, Lucía &  Booth, Kevin T & Lachgar, María & Huygen, Patrick & Villamar, Manuela & Mayo, Fernando & Barrio, Luis Carlos & Santos Serrão de Castro, Luciana & Morales, Carmelo & del Castillo, Ignacio & Arellano, Beatriz & Tellería, Dolores & Smith, Richard J.H. & Azaiez, Hela & Moreno Pelayo, Miguel Angel. 2020 .Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants.

https://hdl.handle.net/20.500.12080/39727
dc.contributor.author Morín, Matias
dc.contributor.author Borreguero, Lucía
dc.contributor.author  Booth, Kevin T
dc.contributor.author Lachgar, María
dc.contributor.author Huygen, Patrick
dc.contributor.author Villamar, Manuela
dc.contributor.author Mayo, Fernando
dc.contributor.author Barrio, Luis Carlos
dc.contributor.author Santos Serrão de Castro, Luciana
dc.contributor.author Morales, Carmelo
dc.contributor.author del Castillo, Ignacio
dc.contributor.author Arellano, Beatriz
dc.contributor.author Tellería, Dolores
dc.contributor.author Smith, Richard J.H.
dc.contributor.author Azaiez, Hela
dc.contributor.author Moreno Pelayo, Miguel Angel
dc.date.accessioned 2024-02-12T14:58:27Z
dc.date.available 2024-02-12T14:58:27Z
dc.date.created 2020
dc.date.issued 2020
dc.identifier.uri https://hdl.handle.net/20.500.12080/39727
dc.description.abstract The mutational spectrum of many genes and their contribution to the global prevalence of hereditary hearing loss is still widely unknown. In this study, we have performed the mutational screening of EYA4 gene by DHLPC and NGS in a large cohort of 531 unrelated Spanish probands and one Australian family with autosomal dominant non-syndromic hearing loss (ADNSHL). In total, 9 novel EYA4 variants have been identifed, 3 in the EYA4 variable region (c.160G>T; p.Glu54*, c.781del; p.Thr261Argfs*34 and c.1078C>A; p.Pro360Thr) and 6 in the EYA-HR domain (c.1107G>T; p.Glu369Asp, c.1122G>¿T; p.Trp374Cys, c.1281G>A; p.Glu427Glu, c.1282-1G>A, c.1601C>G; p.S534* and an heterozygous copy number loss encompassing exons 15 to 17). The contribution of EYA4 mutations to ADNSHL in Spain is, therefore, very limited (~1.5%, 8/531). The pathophysiology of some of these novel variants has been explored. Transient expression of the c-myc-tagged EYA4 mutants in mammalian COS7 cells revealed absence of expression of the p.S534* mutant, consistent with a model of haploinsufciency reported for all previously described EYA4 truncating mutations. However, normal expression pattern and translocation to the nucleus were observed for the p.Glu369Asp mutant in presence of SIX1. Complementary in silico analysis suggested that c.1107G>T (p.Glu369Asp), c.1281G>A (p.Glu427Glu) and c.1282-1G>A variants alter normal splicing. Minigene assays in NIH3T3 cells further confrmed that all 3 variants caused exon skipping resulting in frameshifts that lead to premature stop codons. Our study reports the frst likely pathogenic synonymous variant linked to DFNA10 and provide further evidence for haploinsufciency as the common underlying disease-causing mechanism for DFNA10- related hearing loss. es_ES
dc.format application/pdf es_ES
dc.language eng es_ES
dc.rights CC-BY es_ES
dc.rights.uri http://creativecommons.org/licenses/by/4.0/deed.es es_ES
dc.title Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants es_ES
dc.type info:eu-repo/semantics/article es_ES
dc.rights.accessrights info:eu-repo/semantics/openAccess es_ES
dc.identifier.location N/A es_ES


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