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Herborg F, Jensen KL, Tolstoy S, et al. Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease. JCI Insight. 2021;6(18)doi: 10.1172/jci.insight.151496.
Herborg, F., Jensen, K. L., Tolstoy, S., Arends, N. V., Posselt, L. P., Shekar, A., Aguilar, J. I., Lund, V. K., Erreger, K., Rickhag, M., Lycas, M. D., Lonsdale, M. N., Rahbek-Clemmensen, T., Sørensen, A. T., Newman, A. H., Løkkegaard, A., Kjærulff, O., Werge, T., Møller, L. B., Matthies, H. J., Galli, A., Hjermind, L. E., & Gether, U. (2021). Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease. JCI insight, 6(18), . https://doi.org/10.1172/jci.insight.151496
Herborg, Freja, et al. "Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease." JCI insight vol. 6,18 (2021). doi: https://doi.org/10.1172/jci.insight.151496
Herborg F, Jensen KL, Tolstoy S, Arends NV, Posselt LP, Shekar A, Aguilar JI, Lund VK, Erreger K, Rickhag M, Lycas MD, Lonsdale MN, Rahbek-Clemmensen T, Sørensen AT, Newman AH, Løkkegaard A, Kjærulff O, Werge T, Møller LB, Matthies HJ, Galli A, Hjermind LE, Gether U. Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease. JCI Insight. 2021 Sep 22;6(18). doi: 10.1172/jci.insight.151496. PMID: 34375312; PMCID: PMC8492322.
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JCI Insight. 2021 Sep 22;6(18). doi: 10.1172/jci.insight.151496.

Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease.

JCI insight

Freja Herborg, Kathrine L Jensen, Sasha Tolstoy, Natascha V Arends, Leonie P Posselt, Aparna Shekar, Jenny I Aguilar, Viktor K Lund, Kevin Erreger, Mattias Rickhag, Matthew D Lycas, 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

Affiliations

  1. Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  2. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.
  3. Department of Clinical Physiology and Nuclear Medicine, Bispebjerg Hospital, Copenhagen, Denmark.
  4. National Institute on Drug Abuse Intramural Research Program, NIH, Baltimore, Maryland, USA.
  5. Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
  6. Institute of Biological Psychiatry, Mental Health Services Copenhagen, Copenhagen, Denmark.
  7. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
  8. Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark.
  9. Center for Applied Human Genetics, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
  10. Department of Surgery, University of Alabama, Birmingham, Alabama, USA.
  11. Danish Dementia Research Centre, Clinic of Neurogenetics, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  12. Department of Cellular and Molecular Medicine, Section of Neurogenetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

PMID: 34375312 PMCID: PMC8492322 DOI: 10.1172/jci.insight.151496

Abstract

Dysfunctional dopaminergic neurotransmission is central to movement disorders and mental diseases. The dopamine transporter (DAT) regulates extracellular dopamine levels, but the genetic and mechanistic link between DAT function and dopamine-related pathologies is not clear. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here, we use clinical information, neuroimaging, and large-scale exome-sequencing data to uncover the occurrence and phenotypic spectrum of a DAT coding variant, DAT-K619N, which localizes to the critical C-terminal PSD-95/Discs-large/ZO-1 homology-binding motif of human DAT (hDAT). We identified the rare but recurrent hDAT-K619N variant in exome-sequenced samples of patients with neuropsychiatric diseases and a patient with early-onset neurodegenerative parkinsonism and comorbid neuropsychiatric disease. In cell cultures, hDAT-K619N displayed reduced uptake capacity, decreased surface expression, and accelerated turnover. Unilateral expression in mouse nigrostriatal neurons revealed differential effects of hDAT-K619N and hDAT-WT on dopamine-directed behaviors, and hDAT-K619N expression in Drosophila led to impairments in dopamine transmission with accompanying hyperlocomotion and age-dependent disturbances of the negative geotactic response. Moreover, cellular studies and viral expression of hDAT-K619N in mice demonstrated a dominant-negative effect of the hDAT-K619N mutant. Summarized, our results suggest that hDAT-K619N can effectuate dopamine dysfunction of pathological relevance in a dominant-negative manner.

Keywords: Cell Biology; Molecular genetics; Neuroscience; Parkinson disease; Psychiatric diseases

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