A DNA variant within the MYO7A promoter regulates YY1 transcription factor binding and gene expression serving as a potential dominant DFNA11 auditory genetic modifier.

Mutations within MYO7A can lead to recessive and dominant forms of inherited hearing loss. We previously identified a large pedigree (referred to as the HL2 family) with hearing loss that first impacts the low and mid frequencies segregating a dominant MYO7A mutation in exon 17 at DNA residue G2164C. The MYO7A(G2164C) mutation predicts a nonconservative glycine-to-arginine (G722R) amino acid substitution at a highly conserved glycine residue. The degree of low and mid frequency hearing loss varies markedly in the family, suggesting the presence of a genetic modifier that either rescues or exacerbates the primary MYO7A(G2164C) mutation. Here we describe a single nucleotide polymorphism (SNP) T/C at position -4128 in the wild-type MYO7A promoter allele that sorts with the degree of hearing loss severity in the pedigree. Electrophoretic mobility shift assay analysis indicates that the SNP differentially regulates the binding of the YY1 transcription factor with the T(-4128) allele creating an YY1 binding site. Immunocytochemistry demonstrates that Yy1 is expressed in hair cell nuclei within the cochlea. Given that Myo7a is also expressed in cochlear hair cells, Yy1 shows the appropriate localization to regulate Myo7a transcription within the inner ear. YY1 appears to be acting as a transcriptional repressor as the MYO7A promoter allele containing the T(-4128) SNP drives 41 and 46% less reporter gene expression compared with the C(-4128) SNP in the ARPE-19 and HeLa cell lines, respectively. The T(-4128) SNP may be contributing to the severe hearing loss phenotype in the HL2 pedigree by reducing expression of the wild-type MYO7A allele.