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Cytoplasmic Mislocalization of POU3F4 Due to Novel Mutations Leads to Deafness in Humans and Mice

Authors

  • Thomas Parzefall,

    1. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Current affiliation:
    1. Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
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    • These two authors contributed equally to this work.

  • Shaked Shivatzki,

    1. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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    • These two authors contributed equally to this work.

  • Danielle R. Lenz,

    1. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Birgit Rathkolb,

    1. Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität, Munich, Germany
    2. Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
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  • Kathy Ushakov,

    1. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Daphne Karfunkel,

    1. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Yisgav Shapira,

    1. Department of Otolaryngology, Head & Neck Surgery, Sheba Medical Center, Tel Hashomer, Israel
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  • Michael Wolf,

    1. Department of Otolaryngology, Head & Neck Surgery, Sheba Medical Center, Tel Hashomer, Israel
    2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Manuela Mohr,

    1. Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität, Munich, Germany
    Current affiliation:
    1. Veterinary Surgery, Grafrath, Germany
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  • Eckhard Wolf,

    1. Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität, Munich, Germany
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  • Sibylle Sabrautzki,

    1. Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
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  • Martin Hrabé de Angelis,

    1. Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
    2. Technische Universität München, Center of Life and Food Science, Freising-Weihenstephan, Germany
    3. German Center for Diabetes Research (DZD), Neuherberg, Germany
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  • Moshe Frydman,

    1. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    2. Danek Gertner Institute for Medical Genetics, Sheba Medical Center, Tel Hashomer, Israel
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  • Zippora Brownstein,

    1. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Karen B. Avraham

    Corresponding author
    1. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    • Correspondence to: Karen B. Avraham, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. E-mail: karena@post.tau.ac.il

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  • Communicated by Nobuyoshi Shimizu

  • Contract grant sponsors: European Commission FP6 Integrated Project EUMODIC 037188; the National Institutes of Health (NIDCD) R01DC011835; I-CORE Gene Regulation in Complex Human Disease Center No. 41/11; the Hedrich Charitable Trust; Israel Ministry of Science and Technology; EMBO Molecular Medicine Fellowship AMMF 52–2010; the German Federal Ministry of Education and Research (NGFN-Plus grant No. 01GS0850 and 01GS0851); the Infrafrontier Grant 01KX1012; German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD).

ABSTRACT

POU3F4 is a POU domain transcription factor that is required for hearing. In the ear, POU3F4 is essential for mesenchymal remodeling of the bony labyrinth and is the causative gene for DFNX2 human nonsyndromic deafness. Ear abnormalities underlie this form of deafness, characterized previously in multiple spontaneous, radiation-induced and transgenic mouse mutants. Here, we report three novel mutations in the POU3F4 gene that result in profound hearing loss in both humans and mice. A p.Gln79* mutation was identified in a child from an Israeli family, revealed by massively parallel sequencing (MPS). This strategy demonstrates the strength of MPS for diagnosis with only one affected individual. A second mutation, p.Ile285Argfs*43, was identified by Sanger sequencing. A p.Cys300* mutation was found in an ENU-induced mutant mouse, schwindel (sdl), by positional cloning. The mutation leads to a predicted truncated protein, similar to the human mutations, providing a relevant mouse model. The p.Ile285Argfs*43 and p.Cys300* mutations lead to a shift of Pou3f4 nuclear localization to the cytoplasm, demonstrated in cellular localization studies and in the inner ears of the mutant mice. The discovery of these mutations facilitates a deeper comprehension of the molecular basis of inner ear defects due to mutations in the POU3F4 transcription factor.

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