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Cited by 302Hearing, Cochlea, Tinnitus, GeneticsMicroRNA in disease regulationCongenital Ear and Nasal Anomalies

An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice

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Lewis, Morag A, Quint, Elizabeth, Glazier, Anne M, Fuchs, Helmut, De Angelis, Martin Hrabé, Langford, Cordelia, van Dongen, Stijn, Abreu-Goodger, Cei +6 more·2009·Nature Genetics
DOI 10.1038/ng.369PMC PMC2705913
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Abstract

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.

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  • Point mutations within the seed region of miR-96 cause autosomal dominant non-syndromic sensorineural hearing loss in two Spanish families and in a mouse model of NSHL.

    “Recently, point mutations within the seed region of miR-96 were reported in two Spanish families with autosomal dominant non-syndromic sensorineural hearing loss (NSHL) and in a mouse model of NSHL.”

    From A novel mutation within the MIR96 gene causes non-syndromic inherited hearing loss in an Italian family by altering pre-miRNA processing (2012) · cites this paper as [15]

    The paper reports a seed-region miR-96 mutation associated with progressive hearing loss in its diminuendo mouse model. It also reports two different seed-region changes in humans with progressive hearing loss, citing an accompanying study (discussion passage; page unavailable). Our copy does not establish that the human cases were two Spanish families or had autosomal dominant sensorineural hearing loss, and it describes the mouse trait as semi-dominant rather than specifically non-syndromic. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The diminuendo mouse, which carries a mutant miR-96 seed region, does not have a major effect on miR-96 expression levels.

    “In this respect, it should be recalled that the diminuendo mouse, which carries a mutant miR-96 seed region, does not have a major effect on miR-96 expression levels (15).”

    From A novel mutation within the MIR96 gene causes non-syndromic inherited hearing loss in an Italian family by altering pre-miRNA processing (2012) · cites this paper as [15]

    The passage on the Mirn96 cluster (page unavailable) reports mature miR-96 expression in hair cells of both wild-type and homozygous diminuendo mice, and suggests the mutation does not have a major effect on miRNA processing or export. It does not directly compare miR-96 expression levels, so the claim is more specific than the evidence. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Tight regulation of miR-96 levels within the vertebrate inner ear is crucial for the correct function and development of hair cells.

    “Indeed, tight regulation of miR-96 levels within the vertebrate inner ear seems to be crucial for the correct function and development of hair cells, as demonstrated by knockdown experiments in zebrafish (11) and by the phenotypic differences between the heterozygous and the homozygous diminuendo mice (15,16).”

    From A novel mutation within the MIR96 gene causes non-syndromic inherited hearing loss in an Italian family by altering pre-miRNA processing (2012) · cites this paper as [15]

    The paper reports different hair-cell defects and hearing phenotypes in heterozygous and homozygous diminuendo mice (passage 8; section labeled Abstract, page unavailable), supporting the part attributed to the mouse study. It studies a mutation in miR-96’s seed region, however, and reports mature miRNAs in both wild-type and mutant hair cells (passage 1); it does not establish that tight regulation of miR-96 levels causes those differences. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Besides gene dosage abnormalities, single nucleotide substitutions in two miRNA genes have been identified in human diseases: MIR96 mutations in autosomal dominant deafness 50 and MIR184 mutations in EDICT syndrome and familial and sporadic cases of keratoconus.

    “Besides gene dosage abnormalities37,38, single nucleotide substitutions in two miRNA genes have been identified in human diseases: MIR96 mutations in autosomal dominant deafness 50 (#613704) and MIR184 mutations in EDICT syndrome (#614303) and familial and sporadic cases of keratoconus1–5,39.”

    From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [39]

    The paper’s discussion reports two single-base changes in the miR-96 seed region in humans with progressive hearing loss, supporting the MIR96 portion of the claim. It does not identify autosomal dominant deafness 50 or address MIR184, EDICT syndrome, or keratoconus. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 30

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Cited by

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Authors
Lewis, M. A., Quint, E., Glazier, A. M., Fuchs, H., De Angelis, M. H., Langford, C., van Dongen, S., Abreu-Goodger, C., Piipari, M., Redshaw, N., Dalmay, T., Moreno-Pelayo, M. A., Enright, A. J., & Steel, K. P.
Affiliations
  • Wellcome Sanger Institute (GB)
  • MRC Institute of Hearing Research (GB)
  • Helmholtz Munich (DE)
  • University of East Anglia (GB)
Corresponding author
Steel, Karen P
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2009-04-12
Volume
41
Issue
5
Pages
614-618
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.369
PMC
PMC2705913
OpenAlex
W2031927417
Cited by
302
References
2
Citations by year
2026: 4 · 2025: 6 · 2024: 16 · 2023: 8 · 2022: 7 · 2021: 12 · 2020: 10 · 2019: 17 · 2018: 15 · 2017: 20 · 2016: 17 · 2015: 15 · 2014: 23 · 2013: 22 · 2012: 38
FWCI
16.61
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
  • Site cant be reached (submittedVersion)
  • UEA Digital Repository (University of East Anglia) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Wellcome Trust (077198, 077189)
  • Medical Research Council (MC_qA137918)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Genetics › Congenital Ear and Nasal Anomalies
Keywords
miR-96, progressive hearing loss, hair cell degeneration, cochlear dysfunction, gene expression profiling, SLC26A5, oxidative coupling of methane, GFI1, PTPRQ
MeSH terms
Animals, Base Sequence, DNA Mutational Analysis, Ethylnitrosourea, Hair Cells, Auditory, Heterozygote, Mice, Inbred C57BL, Mice, Inbred Strains, Molecular Sequence Data, Mutation, Transfection, Hearing Loss, MicroRNAs, Mice

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