A DNA Variant within the MYO7A Promoter Regulates YY1 Transcription Factor Binding and Gene Expression Serving as a Potential Dominant DFNA11 Auditory Genetic Modifier

摘要: Mutations within MYO7A can lead to recessive and dominant forms of inherited hearing loss. We previously identified a large pedigree (referred as the HL2 family) with loss that first impacts low mid frequencies segregating mutation in exon 17 at DNA residue G2164C. The MYO7AG2164C predicts nonconservative glycine-to-arginine (G722R) amino acid substitution highly conserved glycine residue. degree frequency varies markedly family, suggesting presence genetic modifier either rescues or exacerbates primary mutation. Here we describe single nucleotide polymorphism (SNP) T/C position −4128 wild-type promoter allele sorts severity pedigree. Electrophoretic mobility shift assay analysis indicates SNP differentially regulates binding YY1 transcription factor T−4128 creating an site. Immunocytochemistry demonstrates Yy1 is expressed hair cell nuclei cochlea. Given Myo7a also cochlear cells, shows appropriate localization regulate inner ear. appears be acting transcriptional repressor containing drives 41 46% less reporter gene expression compared C−4128 ARPE-19 HeLa lines, respectively. may contributing severe phenotype by reducing allele.