A mutation in Nischarin causes otitis media via LIMK1 and NF-kappa B pathways

Michael Crompton, Tom Purnell, Hayley E. Tyrer, Andrew Parker, Greg Ball, Rachel E. Hardisty-Hughes, Richard Gale, Debbie Williams, Charlotte H. Dean, Michelle M. Simon, Ann-Marie Mallon, Sara Wells, Mahmood F. Bhutta, Martin J. Burton, Hilda Tateossian, Steve D. M. Brown

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    2 Citations (Scopus)

    Abstract

    Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM. The causal mutation was identified as a missense change, L972P, in the Nischarin (NISCH) gene. edison mice develop a serous or granulocytic effusion, increasingly macrophage and neutrophil rich with age, along with a thickened, inflamed mucoperiosteum. We also identified a second hypomorphic allele, V33A, with only modest increases in auditory thresholds and reduced incidence of OM. NISCH interacts with several proteins, including ITGA5 that is thought to have a role in modulating VEGF-induced angiogenesis and vascularization. We identified a significant genetic interaction between Nisch and Itga5; mice heterozygous for Itga5-null and homozygous for edison mutations display a significantly increased penetrance and severity of chronic OM. In order to understand the pathological mechanisms underlying the OM phenotype, we studied interacting partners to NISCH along with downstream signalling molecules in the middle ear epithelia of edison mouse. Our analysis implicates PAK1 and RAC1, and downstream signalling in LIMK1 and NF-kappa B pathways in the development of chronic OM.

    Original languageEnglish
    Article number1006969
    Number of pages28
    JournalPLoS Genetics
    Volume13
    Issue number8
    DOIs
    Publication statusPublished - Aug 2017

    Cite this

    Crompton, M., Purnell, T., Tyrer, H. E., Parker, A., Ball, G., Hardisty-Hughes, R. E., ... Brown, S. D. M. (2017). A mutation in Nischarin causes otitis media via LIMK1 and NF-kappa B pathways. PLoS Genetics, 13(8), [1006969]. https://doi.org/10.1371/journal.pgen.1006969
    Crompton, Michael ; Purnell, Tom ; Tyrer, Hayley E. ; Parker, Andrew ; Ball, Greg ; Hardisty-Hughes, Rachel E. ; Gale, Richard ; Williams, Debbie ; Dean, Charlotte H. ; Simon, Michelle M. ; Mallon, Ann-Marie ; Wells, Sara ; Bhutta, Mahmood F. ; Burton, Martin J. ; Tateossian, Hilda ; Brown, Steve D. M. / A mutation in Nischarin causes otitis media via LIMK1 and NF-kappa B pathways. In: PLoS Genetics. 2017 ; Vol. 13, No. 8.
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    title = "A mutation in Nischarin causes otitis media via LIMK1 and NF-kappa B pathways",
    abstract = "Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM. The causal mutation was identified as a missense change, L972P, in the Nischarin (NISCH) gene. edison mice develop a serous or granulocytic effusion, increasingly macrophage and neutrophil rich with age, along with a thickened, inflamed mucoperiosteum. We also identified a second hypomorphic allele, V33A, with only modest increases in auditory thresholds and reduced incidence of OM. NISCH interacts with several proteins, including ITGA5 that is thought to have a role in modulating VEGF-induced angiogenesis and vascularization. We identified a significant genetic interaction between Nisch and Itga5; mice heterozygous for Itga5-null and homozygous for edison mutations display a significantly increased penetrance and severity of chronic OM. In order to understand the pathological mechanisms underlying the OM phenotype, we studied interacting partners to NISCH along with downstream signalling molecules in the middle ear epithelia of edison mouse. Our analysis implicates PAK1 and RAC1, and downstream signalling in LIMK1 and NF-kappa B pathways in the development of chronic OM.",
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    author = "Michael Crompton and Tom Purnell and Tyrer, {Hayley E.} and Andrew Parker and Greg Ball and Hardisty-Hughes, {Rachel E.} and Richard Gale and Debbie Williams and Dean, {Charlotte H.} and Simon, {Michelle M.} and Ann-Marie Mallon and Sara Wells and Bhutta, {Mahmood F.} and Burton, {Martin J.} and Hilda Tateossian and Brown, {Steve D. M.}",
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    Crompton, M, Purnell, T, Tyrer, HE, Parker, A, Ball, G, Hardisty-Hughes, RE, Gale, R, Williams, D, Dean, CH, Simon, MM, Mallon, A-M, Wells, S, Bhutta, MF, Burton, MJ, Tateossian, H & Brown, SDM 2017, 'A mutation in Nischarin causes otitis media via LIMK1 and NF-kappa B pathways' PLoS Genetics, vol. 13, no. 8, 1006969. https://doi.org/10.1371/journal.pgen.1006969

    A mutation in Nischarin causes otitis media via LIMK1 and NF-kappa B pathways. / Crompton, Michael; Purnell, Tom; Tyrer, Hayley E.; Parker, Andrew; Ball, Greg; Hardisty-Hughes, Rachel E.; Gale, Richard; Williams, Debbie; Dean, Charlotte H.; Simon, Michelle M.; Mallon, Ann-Marie; Wells, Sara; Bhutta, Mahmood F.; Burton, Martin J.; Tateossian, Hilda; Brown, Steve D. M.

    In: PLoS Genetics, Vol. 13, No. 8, 1006969, 08.2017.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - A mutation in Nischarin causes otitis media via LIMK1 and NF-kappa B pathways

    AU - Crompton, Michael

    AU - Purnell, Tom

    AU - Tyrer, Hayley E.

    AU - Parker, Andrew

    AU - Ball, Greg

    AU - Hardisty-Hughes, Rachel E.

    AU - Gale, Richard

    AU - Williams, Debbie

    AU - Dean, Charlotte H.

    AU - Simon, Michelle M.

    AU - Mallon, Ann-Marie

    AU - Wells, Sara

    AU - Bhutta, Mahmood F.

    AU - Burton, Martin J.

    AU - Tateossian, Hilda

    AU - Brown, Steve D. M.

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    Y1 - 2017/8

    N2 - Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM. The causal mutation was identified as a missense change, L972P, in the Nischarin (NISCH) gene. edison mice develop a serous or granulocytic effusion, increasingly macrophage and neutrophil rich with age, along with a thickened, inflamed mucoperiosteum. We also identified a second hypomorphic allele, V33A, with only modest increases in auditory thresholds and reduced incidence of OM. NISCH interacts with several proteins, including ITGA5 that is thought to have a role in modulating VEGF-induced angiogenesis and vascularization. We identified a significant genetic interaction between Nisch and Itga5; mice heterozygous for Itga5-null and homozygous for edison mutations display a significantly increased penetrance and severity of chronic OM. In order to understand the pathological mechanisms underlying the OM phenotype, we studied interacting partners to NISCH along with downstream signalling molecules in the middle ear epithelia of edison mouse. Our analysis implicates PAK1 and RAC1, and downstream signalling in LIMK1 and NF-kappa B pathways in the development of chronic OM.

    AB - Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM. The causal mutation was identified as a missense change, L972P, in the Nischarin (NISCH) gene. edison mice develop a serous or granulocytic effusion, increasingly macrophage and neutrophil rich with age, along with a thickened, inflamed mucoperiosteum. We also identified a second hypomorphic allele, V33A, with only modest increases in auditory thresholds and reduced incidence of OM. NISCH interacts with several proteins, including ITGA5 that is thought to have a role in modulating VEGF-induced angiogenesis and vascularization. We identified a significant genetic interaction between Nisch and Itga5; mice heterozygous for Itga5-null and homozygous for edison mutations display a significantly increased penetrance and severity of chronic OM. In order to understand the pathological mechanisms underlying the OM phenotype, we studied interacting partners to NISCH along with downstream signalling molecules in the middle ear epithelia of edison mouse. Our analysis implicates PAK1 and RAC1, and downstream signalling in LIMK1 and NF-kappa B pathways in the development of chronic OM.

    KW - CELL-MIGRATION

    KW - P21-ACTIVATED KINASES

    KW - EPITHELIAL-CELLS

    KW - ACTIVATION

    KW - MOUSE

    KW - GENE

    KW - PROTEIN

    KW - RAC1

    KW - PAK

    KW - PHOSPHORYLATION

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    DO - 10.1371/journal.pgen.1006969

    M3 - Article

    VL - 13

    JO - PLoS Genetics

    JF - PLoS Genetics

    SN - 1553-7390

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    M1 - 1006969

    ER -

    Crompton M, Purnell T, Tyrer HE, Parker A, Ball G, Hardisty-Hughes RE et al. A mutation in Nischarin causes otitis media via LIMK1 and NF-kappa B pathways. PLoS Genetics. 2017 Aug;13(8). 1006969. https://doi.org/10.1371/journal.pgen.1006969