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A dominant-negative variant in the dopamine transporter PDZ-binding motif is linked to parkinsonism and neuropsychiatric disease

View ORCID ProfileFreja Herborg, Kathrine L. Jensen, Sasha Tolstoy, Natascha V. Arends, Leonie P. Posselt, Aparna Shekar, Jenny Aguilar, Viktor K. Lund, Kevin Erreger, Mattias Rickhag, Matthew D. Lykas, Markus N. Lonsdale, Troels Rahbek-Clemmensen, Andreas T. Sørensen, Amy H. Newman, Annemette Løkkegaard, Ole Kjærulff, Thomas Werge, Lisbeth B. Møller, Heinrich JG Matthies, Aurelio Galli, Lena E. Hjermind, Ulrik Gether
doi: https://doi.org/10.1101/2020.10.12.336461
Freja Herborg
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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  • ORCID record for Freja Herborg
  • For correspondence: frejahh@sund.ku.dk gether@sund.ku.dk
Kathrine L. Jensen
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Sasha Tolstoy
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Natascha V. Arends
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Leonie P. Posselt
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Aparna Shekar
2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, USA
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Jenny Aguilar
2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, USA
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Viktor K. Lund
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Kevin Erreger
2Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, USA
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Mattias Rickhag
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Matthew D. Lykas
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Markus N. Lonsdale
3Department of Clinical Physiology & Nuclear Medicine, Bispebjerg Hospital, Copenhagen, Denmark
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Troels Rahbek-Clemmensen
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Andreas T. Sørensen
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Amy H. Newman
4National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, USA
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Annemette Løkkegaard
5Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Denmark
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Ole Kjærulff
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Thomas Werge
6Institute of Biological Psychiatry, Mental Health Services Copenhagen; Department of Clinical Medicine, University of Copenhagen; and The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark
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Lisbeth B. Møller
7Center for Applied Human Genetics, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark
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Heinrich JG Matthies
8Department of Surgery, University of Alabama, Birmingham, USA
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Aurelio Galli
8Department of Surgery, University of Alabama, Birmingham, USA
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Lena E. Hjermind
9Danish Dementia Research Centre, Clinic of Neurogenetics, Department of Neurology, Rigshospitalet, Copenhagen University Hospital and Department of Cellular and Molecular Medicine, Section of Neurogenetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Ulrik Gether
1Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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  • For correspondence: frejahh@sund.ku.dk gether@sund.ku.dk
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Abstract

Dopaminergic dysfunction is central to movement disorders and mental diseases. The dopamine transporter (DAT) is essential for the regulation of extracellular dopamine but the genetic and mechanistic link between DAT function and dopamine-related pathologies remains elusive. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here we identify a novel coding DAT variant, DAT-K619N, in a patient with early-onset parkinsonism and comorbid neuropsychiatric disease and in 22 individuals from exome-sequenced samples of neuropsychiatric patients. The variant localizes to the critical C-terminal PDZ-binding motif of DAT and causes reduced uptake capacity, decreased surface expression, and accelerated turnover of DAT in vitro. In vivo, we demonstrate that expression of DAT-K619N in mice and dropsophila imposes impairments in dopamine transmission with accompanying changes in dopamine-directed behaviors. Importantly, both cellular studies and viral overexpression of DAT-K619N in mice show that DAT-K619N has a dominant-negative effect which collectively implies that a single dominant-negative genetic DAT variant can confer risk for neuropsychiatric disease and neurodegenerative early-onset parkinsonism.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* On behaf of iPSYCH researchers

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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A dominant-negative variant in the dopamine transporter PDZ-binding motif is linked to parkinsonism and neuropsychiatric disease
Freja Herborg, Kathrine L. Jensen, Sasha Tolstoy, Natascha V. Arends, Leonie P. Posselt, Aparna Shekar, Jenny Aguilar, Viktor K. Lund, Kevin Erreger, Mattias Rickhag, Matthew D. Lykas, Markus N. Lonsdale, Troels Rahbek-Clemmensen, Andreas T. Sørensen, Amy H. Newman, Annemette Løkkegaard, Ole Kjærulff, Thomas Werge, Lisbeth B. Møller, Heinrich JG Matthies, Aurelio Galli, Lena E. Hjermind, Ulrik Gether
bioRxiv 2020.10.12.336461; doi: https://doi.org/10.1101/2020.10.12.336461
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A dominant-negative variant in the dopamine transporter PDZ-binding motif is linked to parkinsonism and neuropsychiatric disease
Freja Herborg, Kathrine L. Jensen, Sasha Tolstoy, Natascha V. Arends, Leonie P. Posselt, Aparna Shekar, Jenny Aguilar, Viktor K. Lund, Kevin Erreger, Mattias Rickhag, Matthew D. Lykas, Markus N. Lonsdale, Troels Rahbek-Clemmensen, Andreas T. Sørensen, Amy H. Newman, Annemette Løkkegaard, Ole Kjærulff, Thomas Werge, Lisbeth B. Møller, Heinrich JG Matthies, Aurelio Galli, Lena E. Hjermind, Ulrik Gether
bioRxiv 2020.10.12.336461; doi: https://doi.org/10.1101/2020.10.12.336461

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