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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\u2013binding 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\n                    <jats:italic>Drosophila<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.151496","type":"journal-article","created":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T12:07:13Z","timestamp":1628597233000},"source":"Crossref","is-referenced-by-count":21,"title":["Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0159-4598","authenticated-orcid":true,"given":"Freja","family":"Herborg","sequence":"first","affiliation":[{"name":"Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathrine 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