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

摘要: The mutational spectrum of many genes and their contribution to the global prevalence hereditary hearing loss is still widely unknown. In this study, we have performed screening EYA4 gene by DHLPC NGS in a large cohort 531 unrelated Spanish probands one Australian family with autosomal dominant non-syndromic (ADNSHL). total, 9 novel variants been identified, 3 variable region (c.160G > T; p.Glu54*, c.781del; p.Thr261Argfs*34 c.1078C > A; p.Pro360Thr) 6 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* an heterozygous copy number encompassing exons 15 17). mutations ADNSHL Spain is, therefore, very limited (~1.5%, 8/531). pathophysiology some these has explored. Transient expression c-myc-tagged mutants mammalian COS7 cells revealed absence mutant, consistent model haploinsufficiency reported for all previously described truncating mutations. However, normal pattern translocation nucleus were observed p.Glu369Asp mutant presence SIX1. Complementary silico analysis suggested that c.1107G > T (p.Glu369Asp), c.1281G > A (p.Glu427Glu) c.1282-1G > A alter splicing. Minigene assays NIH3T3 further confirmed caused exon skipping resulting frameshifts lead premature stop codons. Our study reports first likely pathogenic synonymous variant linked DFNA10 provide evidence as common underlying disease-causing mechanism DFNA10-related loss.