Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss

Miguel Moreno-Pelayo and colleagues report mutations in the seed region of human miR-96 segregating with progressive hearing loss in two families. In an accompanying paper, Karen Steel and colleagues show that the mouse diminuendo mutant, which also shows progressive hearing loss, carries a similar mutation in the seed region of mouse miR-96. MicroRNAs (miRNAs) bind to complementary sites in their target mRNAs to mediate post-transcriptional repression 1 , 2 , with the specificity of target recognition being crucially dependent on the miRNA seed region 3 . Impaired miRNA target binding resulting from SNPs within mRNA target sites has been shown to lead to pathologies associated with dysregulated gene expression 4 , 5 , 6 , 7 . However, no pathogenic mutations within the mature sequence of a miRNA have been reported so far. Here we show that point mutations in the seed region of miR-96, a miRNA expressed in hair cells of the inner ear 8 , result in autosomal dominant, progressive hearing loss. This is the first study implicating a miRNA in a mendelian disorder. The identified mutations have a strong impact on miR-96 biogenesis and result in a significant reduction of mRNA targeting. We propose that these mutations alter the regulatory role of miR-96 in maintaining gene expression profiles in hair cells required for their normal function.