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MicroRNAs become large in hearing loss

An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice Lewis et al. (2009) Nature Genetics 41 (5): 614–618 Hearing loss is the most common sensory disorder with one in 850 children affected at birth and an increasing prevalence with age (1). The overall number of genes responsible for hearing loss is large encoding proteins with many different functions and is a likely reflection of the complex anatomy and physiology of the ear (http://www.webhost.ua.ac.be/hhh/). About 100 loci have been mapped to non-syndromic hearing loss and a total of 46 genes have been identified. It is estimated that a similar number of genes is still unknown and explains why there is no molecular diagnosis in many cases. Two recent publications by Lewis et al. and Mencia et al. provide strong support for a mutation in microRNA-96 (miR-96) as an underlying cause for progressive hearing loss in humans and the mouse (2, 3). Notably, the mutations discovered in human miR-96 are the first examples of a dysfunctional miRNA causing a human Mendelian disorder. miRNAs are approximately 22 nucleotide (nt) long endogenous non-coding RNAs that influence mRNA stability and translation (Fig. 1) (4). They are transcribed in the nucleus by RNA polymerase II and undergo processing, transport and maturation before loading into the cytoplasmic RNAinduced silencing complex (RISC). The recognition of target mRNAs occurs through a 2–8 nt seed region that binds to complementary sites in the 3′UTR of target mRNAs and is the most important determinant in target recognition and silencing. Mutations that occur in the seed region can have two potential effects. They can either upregulate known target mRNAs or they can lead to the downregulation of novel acquired mRNA targets. In the study by Mencia and coworkers, two Spanish families were identified with autosomal dominant hearing loss on 7q32. In both cases, the underlying mutations represent single nucleotide changes in the highly conserved seed region of miR-96 [family 1: miR-96 (+13 G>A); family 2: miR-96 (+14 C>A); Fig. 2]. Both mutations segregate with the hearing impairment in each family and are not detected in 462 normal-hearing Spanish controls. In the study by Lewis and coworkers a new N -ethyl-N -nitrosurea (ENU)induced mouse mutant, diminuendo, is described with a single nucleotide change (A>T) in the seed region of miR-96. This mutation is located adjacent to the single nucleotide changes observed in the seed region of human miR-96 in family 1 and 2 and provides additional support for a critical role of the seed region in the control of miR-96 function.