Journal article
Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants
Scientific reports, Vol.10(1), pp.6213-6213
04/10/2020
DOI: 10.1038/s41598-020-63256-5
PMCID: PMC7148344
PMID: 32277154
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 > 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 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 > T (p.Glu369Asp), c.1281G > A (p.Glu427Glu) and c.1282-1G > 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.
Details
- Title: Subtitle
- Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants
- Creators
- Matias Morín - Instituto CajalLucía Borreguero - Instituto CajalKevin T Booth - University of IowaMaría Lachgar - Instituto CajalPatrick Huygen - Radboud University Medical CenterManuela Villamar - Instituto CajalFernando Mayo - Instituto CajalLuis Carlos Barrio - Instituto CajalLuciana Santos Serrão de Castro - Instituto CajalCarmelo Morales - Servicio de Otorrinolaringología, Hospital Universitario Marqués de Valdecilla, Santander, SpainIgnacio Del Castillo - Instituto CajalBeatriz Arellano - Hospital Universitario Puerta de Hierro MajadahondaDolores Tellería - Instituto CajalRichard J H Smith - University of IowaHela Azaiez - University of IowaM A Moreno Pelayo - Instituto Cajal
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.10(1), pp.6213-6213
- DOI
- 10.1038/s41598-020-63256-5
- PMID
- 32277154
- PMCID
- PMC7148344
- NLM abbreviation
- Sci Rep
- ISSN
- 2045-2322
- eISSN
- 2045-2322
- Grant note
- R01 DC003544 / NIDCD NIH HHS R01 DC012049 / NIDCD NIH HHS R01 DC002842 / NIDCD NIH HHS L60 MD003721 / NIMHD NIH HHS
- Language
- English
- Date published
- 04/10/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984256934102771
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