Missense dopamine transporter mutations associate with adult parkinsonism and ADHD
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Missense dopamine transporter mutations associate with adult parkinsonism and ADHD. / Hansen, Freja H; Skjørringe, Tina; Yasmeen, Saiqa; Arends, Natascha V; Sahai, Michelle A; Erreger, Kevin; Andreassen, Thorvald F; Holy, Marion; Hamilton, Peter J; Neergheen, Viruna; Karlsborg, Merete; Newman, Amy H; Pope, Simon; Heales, Simon J R; Friberg, Lars; Law, Ian; Pinborg, Lars H; Sitte, Harald H; Loland, Claus; Shi, Lei; Weinstein, Harel; Galli, Aurelio; Hjermind, Lena E; Møller, Lisbeth B; Gether, Ulrik.
In: The Journal of Clinical Investigation, Vol. 124, No. 7, 01.07.2014, p. 3107-20.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Missense dopamine transporter mutations associate with adult parkinsonism and ADHD
AU - Hansen, Freja H
AU - Skjørringe, Tina
AU - Yasmeen, Saiqa
AU - Arends, Natascha V
AU - Sahai, Michelle A
AU - Erreger, Kevin
AU - Andreassen, Thorvald F
AU - Holy, Marion
AU - Hamilton, Peter J
AU - Neergheen, Viruna
AU - Karlsborg, Merete
AU - Newman, Amy H
AU - Pope, Simon
AU - Heales, Simon J R
AU - Friberg, Lars
AU - Law, Ian
AU - Pinborg, Lars H
AU - Sitte, Harald H
AU - Loland, Claus
AU - Shi, Lei
AU - Weinstein, Harel
AU - Galli, Aurelio
AU - Hjermind, Lena E
AU - Møller, Lisbeth B
AU - Gether, Ulrik
PY - 2014/7/1
Y1 - 2014/7/1
N2 - 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.
AB - 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.
U2 - 10.1172/JCI73778
DO - 10.1172/JCI73778
M3 - Journal article
C2 - 24911152
VL - 124
SP - 3107
EP - 3120
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 7
ER -
ID: 119649951