Letter abstract
Nature Genetics
Published online: 12 April 2009 | doi:10.1038/ng.369
An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice
Morag A Lewis1, Elizabeth Quint2, Anne M Glazier1, Helmut Fuchs3, Martin Hrabé De Angelis3, Cordelia Langford1, Stijn van Dongen1, Cei Abreu-Goodger1, Matias Piipari1, Nick Redshaw4, Tamas Dalmay4, Miguel Angel Moreno-Pelayo5,6, Anton J Enright1 & Karen P Steel1,2
Progressive hearing loss is common in the human population, but little is known about the molecular basis. We report a new N-ethyl-N-nitrosurea (ENU)-induced mouse mutant, diminuendo, with a single base change in the seed region of Mirn96. Heterozygotes show progressive loss of hearing and hair cell anomalies, whereas homozygotes have no cochlear responses. Most microRNAs are believed to downregulate target genes by binding to specific sites on their mRNAs, so mutation of the seed should lead to target gene upregulation. Microarray analysis revealed 96 transcripts with significantly altered expression in homozygotes; notably, Slc26a5, Ocm, Gfi1, Ptprq and Pitpnm1 were downregulated. Hypergeometric P-value analysis showed that hundreds of genes were upregulated in mutants. Different genes, with target sites complementary to the mutant seed, were downregulated. This is the first microRNA found associated with deafness, and diminuendo represents a model for understanding and potentially moderating progressive hair cell degeneration in hearing loss more generally.
- Wellcome Trust Sanger Institute, Hinxton, UK.
- Medical Research Council, Institute of Hearing Research, Nottingham, UK.
- GSF National Research Center for Environment and Health, Munich, Germany.
- School of Biological Sciences, University of East Anglia, Norwich, UK.
- Unidad de Genética Molecular, Hospital Ramón y Cajal, Madrid, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
Correspondence to: Karen P Steel1,2 e-mail: kps@sanger.ac.uk