Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants. Morín, M.; Borreguero, L.; Booth, K. T.; Lachgar, M.; Huygen, P.; Villamar, M.; Mayo, F.; Barrio, L. C.; Santos Serrão de Castro, L.; Morales, C.; Del Castillo, I.; Arellano, B.; Tellería, D.; Smith, R. J. H.; Azaiez, H.; and Moreno Pelayo, M. A. Scientific Reports, 10(1):6213, April, 2020.
doi  abstract   bibtex   
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 identified, 3 in the EYA4 variable region (c.160G \textgreater T; p.Glu54*, c.781del; p.Thr261Argfs*34 and c.1078C \textgreater A; p.Pro360Thr) and 6 in the EYA-HR domain (c.1107G \textgreater T; p.Glu369Asp, c.1122G \textgreater T; p.Trp374Cys, c.1281G \textgreater A; p.Glu427Glu, c.1282-1G \textgreater A, c.1601C \textgreater 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 (\textasciitilde1.5%, 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 haploinsufficiency 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 \textgreater T (p.Glu369Asp), c.1281G \textgreater A (p.Glu427Glu) and c.1282-1G \textgreater A variants alter normal splicing. Minigene assays in NIH3T3 cells further confirmed that all 3 variants caused exon skipping resulting in frameshifts that lead to premature stop codons. Our study reports the first likely pathogenic synonymous variant linked to DFNA10 and provide further evidence for haploinsufficiency as the common underlying disease-causing mechanism for DFNA10-related hearing loss.
@article{morin_insights_2020-1,
	title = {Insights into the pathophysiology of {DFNA10} hearing loss associated with novel {EYA4} variants},
	volume = {10},
	issn = {2045-2322},
	doi = {10.1038/s41598-020-63256-5},
	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 identified, 3 in the EYA4 variable region (c.160G {\textgreater} T; p.Glu54*, c.781del; p.Thr261Argfs*34 and c.1078C {\textgreater} A; p.Pro360Thr) and 6 in the EYA-HR domain (c.1107G {\textgreater} T; p.Glu369Asp, c.1122G {\textgreater} T; p.Trp374Cys, c.1281G {\textgreater} A; p.Glu427Glu, c.1282-1G {\textgreater} A, c.1601C {\textgreater} 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 ({\textasciitilde}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 haploinsufficiency 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 {\textgreater} T (p.Glu369Asp), c.1281G {\textgreater} A (p.Glu427Glu) and c.1282-1G {\textgreater} A variants alter normal splicing. Minigene assays in NIH3T3 cells further confirmed that all 3 variants caused exon skipping resulting in frameshifts that lead to premature stop codons. Our study reports the first likely pathogenic synonymous variant linked to DFNA10 and provide further evidence for haploinsufficiency as the common underlying disease-causing mechanism for DFNA10-related hearing loss.},
	language = {eng},
	number = {1},
	journal = {Scientific Reports},
	author = {Morín, Matias and Borreguero, Lucía and Booth, Kevin T. and Lachgar, María and Huygen, Patrick and Villamar, Manuela and Mayo, Fernando and Barrio, Luis Carlos and Santos Serrão de Castro, Luciana and Morales, Carmelo and Del Castillo, Ignacio and Arellano, Beatriz and Tellería, Dolores and Smith, Richard J. H. and Azaiez, Hela and Moreno Pelayo, M. A.},
	month = apr,
	year = {2020},
	pmid = {32277154},
	pmcid = {PMC7148344},
	pages = {6213},
}
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