PT  - JOURNAL ARTICLE
AU  - Freja Herborg
AU  - Kathrine L. Jensen
AU  - Sasha Tolstoy
AU  - Natascha V. Arends
AU  - Leonie P. Posselt
AU  - Aparna Shekar
AU  - Jenny Aguilar
AU  - Viktor K. Lund
AU  - Kevin Erreger
AU  - Mattias Rickhag
AU  - Matthew D. Lykas
AU  - Markus N. Lonsdale
AU  - Troels Rahbek-Clemmensen
AU  - Andreas T. Sørensen
AU  - Amy H. Newman
AU  - Annemette Løkkegaard
AU  - Ole Kjærulff
AU  - Thomas Werge
AU  - Lisbeth B. Møller
AU  - Heinrich JG Matthies
AU  - Aurelio Galli
AU  - Lena E. Hjermind
AU  - Ulrik Gether
TI  - A dominant-negative variant in the dopamine transporter PDZ-binding motif is linked to parkinsonism and neuropsychiatric disease
AID  - 10.1101/2020.10.12.336461
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.12.336461
4099  - http://biorxiv.org/content/early/2020/10/12/2020.10.12.336461.short
4100  - http://biorxiv.org/content/early/2020/10/12/2020.10.12.336461.full
AB  - 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 StatementThe authors have declared no competing interest.