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

Abstract

MicroRNAs (miRNAs) bind to complementary sites in their target mRNAs to mediate post-transcriptional repression, with the specificity of target recognition being crucially dependent on the miRNA seed region. Impaired miRNA target binding resulting from SNPs within mRNA target sites has been shown to lead to pathologies associated with dysregulated gene expression. 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, 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.

Improving hearing loss gene testing: a systematic review of gene evidence toward more efficient next-generation sequencing–based diagnostic testing and interpretation

“…10 The study lacked segregation or functional data to support pathogenicity of any of the variants identified, failing to support a gene-disease association between MYO1A and 25 and they are thought to regulate sensorineural cell fates in the inner ear. 26 Although three variants in the MIR96 gene have been shown to segregate with disease in three families with autosomaldominant nonsyndromic hearing loss, 27,28 no variants were identified in either MIR182 or MIR183 in patients with hearing loss. A mouse model strongly supports the contribution of MIR96 to hearing loss, 29 though no such evidence has been found for MIR182 and MIR183; their expression as part of a polycistronic transcript in the inner ear is insufficient to assume a functional role for these microRNAs in the auditory process.…”

Gene Expression Gradients along the Tonotopic Axis of the Chicken Auditory Epithelium

“…It is striking that all 22 miRNA gene sets that were significantly enriched showed this directionality. Myriad miRNA have already been shown not only to be expressed in the inner ear (Weston et al 2006;Sacheli et al 2009;Wang et al 2010), but also to play an important role in inner ear development (Friedman et al 2009;Soukup 2009;Soukup et al 2009), function (Lewis et al 2009;Mencía et al 2009), and hair cell regeneration (Frucht et al 2010). The present results suggest a tonotopic gradient in activity and accordingly expression in the chicken BP.…”

Familiar Meniere's disease restricted to 1.48 Mb on chromosome 12p12.3 by allelic and haplotype association

“…[36][37][38][39][40][41][42][43][44][45][46] Point mutations in the seed region of miR-96, an miRNA expressed in hair cells of the inner ear, result in autosomal dominant, progressive hearing loss. 43,47 Mice mutant for several of the target genes for miRNAs exhibit deafness and hair cell degeneration, indicating the importance of this novel gene regulation in hearing loss. 48,49 To date, no intragenic miRNAs are annotated in the region associated with MD in our families.…”