ArticleThe Journal of clinical investigation2014
Missense dopamine transporter mutations associate with adult parkinsonism and ADHD.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers, 1 of them a synthesis that pooled it.
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Who cites it
89 citing papers in PubMed, 1 synthesis or guideline pooled it, 151 citations in OpenAlex.
- Genotype-Phenotype Relations for the Dystonia-Parkinsonism GenesInternational journal of molecular sciences · 2025Pooled it
- Mouse model of atypical DAT deficiency syndrome uncovers dopamine dysfunction associated with parkinsonism and ADHD.The Journal of clinical investigation · 2026Article
- Kappa opioid receptor antagonism restores phosphorylation, trafficking and behavior induced by a disease-associated dopamine transporter variant.Molecular psychiatry · 2025Article
- A Common Cause of ADHD and Bipolar Disorder (BD).Bipolar disorders · 2025Article
- 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
- Dopamine transporter endocytic trafficking: Neuronal mechanisms and potential impact on DA-dependent behaviors.Journal of neurochemistry · 2025Review
- Amphetamine exposure during embryogenesis changes expression and function of the dopamine transporter in Caenorhabditis elegans offspring.Journal of neurochemistry · 2024Article
- Parkinson's disease gene, Synaptojanin1, dysregulates the surface maintenance of the dopamine transporter.NPJ Parkinson's disease · 2024Article
- Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease, and Disease Treatment 2.0.International journal of molecular sciences · 2024Article
- Gene therapy for neurotransmitter-related disorders.Journal of inherited metabolic disease · 2024Review
- Illuminating the monoamine transporters: Fluorescently labelled ligands to study dopamine, serotonin and norepinephrine transporters.Basic & clinical pharmacology & toxicology · 2023Review
- Long-Lasting Epigenetic Changes in the Dopamine Transporter in Adult Animals Exposed to Amphetamine during Embryogenesis: Investigating Behavioral Effects.International journal of molecular sciences · 2023Article
- Review
- Dopamine Transporter Deficient Rodents: Perspectives and Limitations for Neuroscience.Biomolecules · 2023Review
- Positron emission tomography studies in adult patients with attention-deficit/hyperactivity disorder.Japanese journal of radiology · 2023Review
- Persistent binding at dopamine transporters determines sustained psychostimulant effects.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Phenotypes and Genotypes of Inherited Disorders of Biogenic Amine Neurotransmitter Metabolism.Genes · 2023Review
- Overview of the structure and function of the dopamine transporter and its protein interactions.Frontiers in physiology · 2023Review
- Article
29 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
25 authors at 8 institutions in 4 countries.
Funding
Abstract
Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.
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Registered trials
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.