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Early Disruption of Photoreceptor Cell Architecture and Loss of Vision in a Humanized Pig Model of Usher Syndrome

Sophia Grotz, Jessica Schäfer, Kirsten A. Wunderlich, Zdenka Ellederova, Hannah Auch, Andrea Bähr, Petra Runa-Vochozkova, Janet Plutniok, Vanessa Arnold, Taras Ardan, Miroslav Veith, Gianluca Santamaria, Georg Dhom, Wolfgang Hitzl, Barbara Kessler, Mayuko Kurome, Valeri Zakharchenko, Joshua Linnert, Andrea Fischer, Andreas Blutke, Anna Döring, Stepanka Suchankova, Jiri Popelar, Helen May-Simera, Karl-Ludwig Laugwitz, Luk H. Vandenberghe, Eckhard Wolf, Kerstin Nagel-Wolfrum, Jan Motlik, M. Dominik Fischer, Uwe Wolfrum, Nikolai Klymiuk
doi: https://doi.org/10.1101/2021.05.31.446123
Sophia Grotz
1Chair of Molecular Animal Breeding and Biotechnology, LMU Munich, Germany
2Center for Innovative Medical Models, LMU Munich, Germany
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Jessica Schäfer
3Institute of Molecular Physiology, Molecular Cell biology, JGU Mainz, Germany
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Kirsten A. Wunderlich
3Institute of Molecular Physiology, Molecular Cell biology, JGU Mainz, Germany
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Zdenka Ellederova
44Institute of Animal Physiology and Genetics, Czech Academy of Science, Libechov, Czech Republic
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Hannah Auch
1Chair of Molecular Animal Breeding and Biotechnology, LMU Munich, Germany
2Center for Innovative Medical Models, LMU Munich, Germany
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Andrea Bähr
2Center for Innovative Medical Models, LMU Munich, Germany
5Large Animal Models in Cardiovascular Research, Internal Medical Department I, TU Munich, Germany
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Petra Runa-Vochozkova
5Large Animal Models in Cardiovascular Research, Internal Medical Department I, TU Munich, Germany
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Janet Plutniok
1Chair of Molecular Animal Breeding and Biotechnology, LMU Munich, Germany
3Institute of Molecular Physiology, Molecular Cell biology, JGU Mainz, Germany
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Vanessa Arnold
3Institute of Molecular Physiology, Molecular Cell biology, JGU Mainz, Germany
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Taras Ardan
44Institute of Animal Physiology and Genetics, Czech Academy of Science, Libechov, Czech Republic
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Miroslav Veith
6Ophthalmology Clinic, University Hospital Kralovske Vinohrady, Praha, Czech Republic
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Gianluca Santamaria
5Large Animal Models in Cardiovascular Research, Internal Medical Department I, TU Munich, Germany
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Georg Dhom
1Chair of Molecular Animal Breeding and Biotechnology, LMU Munich, Germany
2Center for Innovative Medical Models, LMU Munich, Germany
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Wolfgang Hitzl
7Biostatistics and Data Science, Paracelsus Medical University, Salzburg, Austria
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Barbara Kessler
1Chair of Molecular Animal Breeding and Biotechnology, LMU Munich, Germany
2Center for Innovative Medical Models, LMU Munich, Germany
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Mayuko Kurome
1Chair of Molecular Animal Breeding and Biotechnology, LMU Munich, Germany
2Center for Innovative Medical Models, LMU Munich, Germany
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Valeri Zakharchenko
1Chair of Molecular Animal Breeding and Biotechnology, LMU Munich, Germany
2Center for Innovative Medical Models, LMU Munich, Germany
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Joshua Linnert
3Institute of Molecular Physiology, Molecular Cell biology, JGU Mainz, Germany
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Andrea Fischer
8Veterinary Faculty, Small Animal Clinics, LMU Munich, Germany
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Andreas Blutke
9Institute of Experimental Genetics, Helmholtz Center Munich, Neuherberg, Germany
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Anna Döring
8Veterinary Faculty, Small Animal Clinics, LMU Munich, Germany
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Stepanka Suchankova
10Institute of Experimental Medicine, Czech Academy of Science, Prague, Czech Republic
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Jiri Popelar
10Institute of Experimental Medicine, Czech Academy of Science, Prague, Czech Republic
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Helen May-Simera
11Institute of Molecular Physiology, Cilia Biology, JGU Mainz;
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Karl-Ludwig Laugwitz
5Large Animal Models in Cardiovascular Research, Internal Medical Department I, TU Munich, Germany
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Luk H. Vandenberghe
12Centre for Ophthalmology, University of Tübingen, Tübingen, Germany; Oxford Eye Hospital, Oxford University NHS Foundation Trust, Oxford, UK & Nuffield Laboratory of Ophthalmology, NDCN, University of Oxford, Oxford, UK
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Eckhard Wolf
1Chair of Molecular Animal Breeding and Biotechnology, LMU Munich, Germany
2Center for Innovative Medical Models, LMU Munich, Germany
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Kerstin Nagel-Wolfrum
3Institute of Molecular Physiology, Molecular Cell biology, JGU Mainz, Germany
11Institute of Molecular Physiology, Cilia Biology, JGU Mainz;
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Jan Motlik
44Institute of Animal Physiology and Genetics, Czech Academy of Science, Libechov, Czech Republic
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M. Dominik Fischer
12Centre for Ophthalmology, University of Tübingen, Tübingen, Germany; Oxford Eye Hospital, Oxford University NHS Foundation Trust, Oxford, UK & Nuffield Laboratory of Ophthalmology, NDCN, University of Oxford, Oxford, UK
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Uwe Wolfrum
3Institute of Molecular Physiology, Molecular Cell biology, JGU Mainz, Germany
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  • For correspondence: n.klymiuk@tum.de wolfrum@uni-mainz.de
Nikolai Klymiuk
2Center for Innovative Medical Models, LMU Munich, Germany
5Large Animal Models in Cardiovascular Research, Internal Medical Department I, TU Munich, Germany
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  • For correspondence: n.klymiuk@tum.de wolfrum@uni-mainz.de
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Abstract

Usher syndrome (USH) is the most common form of monogenic deaf-blindness. Loss of vision is untreatable and, so far, there are no suitable animal models for testing therapeutic strategies. By introducing a human mutation into the harmonin-encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Primary cells from those animals and USH1C patients showed significantly elongated primary cilia, compared to wild-type, confirming the nature of USH as a true and general ciliopathy and proving the therapeutic capacity of gene supplementation and gene repair approaches.

Competing Interest Statement

The authors have declared no competing interest.

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Early Disruption of Photoreceptor Cell Architecture and Loss of Vision in a Humanized Pig Model of Usher Syndrome
Sophia Grotz, Jessica Schäfer, Kirsten A. Wunderlich, Zdenka Ellederova, Hannah Auch, Andrea Bähr, Petra Runa-Vochozkova, Janet Plutniok, Vanessa Arnold, Taras Ardan, Miroslav Veith, Gianluca Santamaria, Georg Dhom, Wolfgang Hitzl, Barbara Kessler, Mayuko Kurome, Valeri Zakharchenko, Joshua Linnert, Andrea Fischer, Andreas Blutke, Anna Döring, Stepanka Suchankova, Jiri Popelar, Helen May-Simera, Karl-Ludwig Laugwitz, Luk H. Vandenberghe, Eckhard Wolf, Kerstin Nagel-Wolfrum, Jan Motlik, M. Dominik Fischer, Uwe Wolfrum, Nikolai Klymiuk
bioRxiv 2021.05.31.446123; doi: https://doi.org/10.1101/2021.05.31.446123
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Early Disruption of Photoreceptor Cell Architecture and Loss of Vision in a Humanized Pig Model of Usher Syndrome
Sophia Grotz, Jessica Schäfer, Kirsten A. Wunderlich, Zdenka Ellederova, Hannah Auch, Andrea Bähr, Petra Runa-Vochozkova, Janet Plutniok, Vanessa Arnold, Taras Ardan, Miroslav Veith, Gianluca Santamaria, Georg Dhom, Wolfgang Hitzl, Barbara Kessler, Mayuko Kurome, Valeri Zakharchenko, Joshua Linnert, Andrea Fischer, Andreas Blutke, Anna Döring, Stepanka Suchankova, Jiri Popelar, Helen May-Simera, Karl-Ludwig Laugwitz, Luk H. Vandenberghe, Eckhard Wolf, Kerstin Nagel-Wolfrum, Jan Motlik, M. Dominik Fischer, Uwe Wolfrum, Nikolai Klymiuk
bioRxiv 2021.05.31.446123; doi: https://doi.org/10.1101/2021.05.31.446123

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