ArticleProceedings of the National Academy of Sciences of the United States of America2014
The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 74 citations in OpenAlex.
- Mouse model of atypical DAT deficiency syndrome uncovers dopamine dysfunction associated with parkinsonism and ADHD.The Journal of clinical investigation · 2026Article
- Multicolor Quantum Dot Tracking Uncovers Phenotypic Rescue of DAT A559V Aberrant Diffusion Upon D2R Antagonism.ACS chemical neuroscience · 2026Article
- The developmental dopamine trajectory hypothesis of ADHD across the lifespan.Frontiers in psychiatry · 2026Article
- Kappa opioid receptor antagonism restores phosphorylation, trafficking and behavior induced by a disease-associated dopamine transporter variant.Molecular psychiatry · 2025Article
- Role of Phosphorylation of Serotonin and Norepinephrine Transporters in Animal Behavior: Relevance to Neuropsychiatric Disorders.International journal of molecular sciences · 2025Review
- The Ins and Outs of Dopamine Transporter Gene Manipulation: In Vivo Models of DAT Dysfunction.Advances in neurobiology · 2025Review
- Causal Mechanisms of Monoamine Transporter Phosphorylation.Advances in neurobiology · 2025Review
- Aberrant extracellular dopamine clearance in the prefrontal cortex exhibits ADHD-like behavior in NCX3 heterozygous mice.The FEBS journal · 2025Article
- Deep-Learning-Based Analysis Reveals a Social Behavior Deficit in Mice Exposed Prenatally to Nicotine.Cells · 2024Article
- The human channel gating-modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome-like phenotype in mice.JCI insight · 2023Article
- Linking autism spectrum disorders and parkinsonism: clinical and genetic association.Annals of clinical and translational neurology · 2023Review
- Article
- Behaviorally penetrant, anomalous dopamine efflux exposes sex and circuit dependent regulation of dopamine transporters.Molecular psychiatry · 2022Article
- Animal Models of ADHD?Current topics in behavioral neurosciences · 2022Article
- Disruption of the PDZ domain-binding motif of the dopamine transporter uniquely alters nanoscale distribution, dopamine homeostasis, and reward motivation.The Journal of biological chemistry · 2021Article
- Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease.JCI insight · 2021Article
- Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons.Brain : a journal of neurology · 2021Article
- Novelty-induced hyperactivity and suppressed cocaine induced locomotor activation in mice lacking threonine 53 phosphorylation of dopamine transporter.Behavioural brain research · 2021Article
- Functional and Biochemical Consequences of Disease Variants in Neurotransmitter Transporters: A Special Emphasis on Folding and Trafficking Deficits.Pharmacology & therapeutics · 2021Review
- Dopaminergic Dysregulation in Syndromic Autism Spectrum Disorders: Insights From Genetic Mouse Models.Frontiers in neural circuits · 2021Review
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.