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Missense dopamine transporter mutations associate with adult parkinsonism and ADHD
Freja H. Hansen, … , Lisbeth B. Møller, Ulrik Gether
Freja H. Hansen, … , Lisbeth B. Møller, Ulrik Gether
Published June 9, 2014
Citation Information: J Clin Invest. 2014;124(7):3107-3120. https://doi.org/10.1172/JCI73778.
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Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

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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.

Authors

Freja H. Hansen, Tina Skjørringe, Saiqa Yasmeen, Natascha V. Arends, Michelle A. Sahai, Kevin Erreger, Thorvald F. Andreassen, Marion Holy, Peter J. Hamilton, Viruna Neergheen, Merete Karlsborg, Amy H. Newman, Simon Pope, Simon J.R. Heales, Lars Friberg, Ian Law, Lars H. Pinborg, Harald H. Sitte, Claus Loland, Lei Shi, Harel Weinstein, Aurelio Galli, Lena E. Hjermind, Lisbeth B. Møller, Ulrik Gether

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Figure 3

Functional characterization of DAT-I312F and DAT-D421N by [3H]-dopamine uptake and [3H]-CFT–binding experiments.

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Functional characterization of DAT-I312F and DAT-D421N by [3H]-dopamine ...
(A) [3H]-dopamine uptake in transiently transfected HEK293 cells. The curves represent average curves from 6 independent experiments, each with triplicate uptake determinations (5 minutes) at the indicated dopamine concentrations. (B) Vmax values of [3H]-dopamine uptake compared with WT. In each experiment, the Vmax values of mutants were normalized to WT. Michaelis-Menten kinetics was applied to fit data. **P < 0.01 and ***P < 0.0001 by 1-sample t test; n = 6. Uptake by DAT-D421N could not be fitted reliably by Michaelis-Menten kinetics and is therefore denoted as not determined (ND). Km values were fitted to 1.7 ± 0.3 μM for WT; 1.8 ± 0.4 μM for DAT-I312F; and 2.1 ± 0.4 for DAT-I312F plus DAT-D421N. (C) Evaluation of [3H]-dopamine uptake at 6.4 μM of dopamine. The uptake was normalized to WT for each experiment. **P < 0.01 and ***P < 0.0001 by 1-sample t test; n = 6. (D) [3H]-CFT binding to transiently transfected COS-7 cells. Curves represent the averages of 4 experiments, each performed in triplicate. Binding data were fitted by nonlinear regression and normalized to WT in each experiment. While DAT-I312F shows preserved binding properties (Kd values [SE intervals] for DAT-I312F and WT were 16.9 [12.1–23.6] nM and 13.7 [12.7–14.8] nM, respectively), no specific binding to DAT-D421N was detected. All data are the means ± SEM. Bmax for WT was 149 ± 39 fmol/105 cells.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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