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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Research Article Neuroscience

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

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 2

Nuclear brain imaging with SPECT and FDG PET.

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Nuclear brain imaging with SPECT and FDG PET. (A) SPECT imaging of DAT. ...
(A) SPECT imaging of DAT. The figure shows images of [123I]FP-CIT binding to DAT in a healthy control (left) and in the proband at 34 years of age (middle) and 43 years of age (right). DAT availability in the striatum, i.e., the ratio of specifically bound radioligand to that of nondisplaceable radioligand, was severely reduced bilaterally and was approximately 35% in 2005 and 15% in 2013 of the expected value in a group of age-matched controls. (B) Transaxial sections through the striatum of the proband with coregistered T1-weighted MRI (left), [18F]-FDG PET (middle), and quantitative statistical comparisons of [18F]-FDG PET (right) with healthy controls showing preserved metabolic activity in the basal ganglia with a slight to moderate reduction (–4 SD; see color scale) in the occipitotemporal junction (red arrows).