Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

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

doi:10.1172/JCI73778

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

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 ShiHarel Weinstein, Aurelio Galli, Lena E Hjermind, Lisbeth B Møller, Ulrik Gether

73 Citations (Scopus)

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.

Original language	English
Journal	The Journal of Clinical Investigation
Volume	124
Issue number	7
Pages (from-to)	3107-20
Number of pages	14
ISSN	0021-9738
DOIs	https://doi.org/10.1172/JCI73778
Publication status	Published - 1 Jul 2014

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Hansen, F. H., Skjørringe, T., Yasmeen, S., Arends, N. V., Sahai, M. A., Erreger, K., Andreassen, T. F., Holy, M., Hamilton, P. J., Neergheen, V., Karlsborg, M., Newman, A. H., Pope, S., Heales, S. J. R., Friberg, L., Law, I., Pinborg, L. H., Sitte, H. H., Loland, C., ... Gether, U. (2014). Missense dopamine transporter mutations associate with adult parkinsonism and ADHD. The Journal of Clinical Investigation, 124(7), 3107-20. https://doi.org/10.1172/JCI73778

Hansen, FH, Skjørringe, T, Yasmeen, S, Arends, NV, Sahai, MA, Erreger, K, Andreassen, TF, Holy, M, Hamilton, PJ, Neergheen, V, Karlsborg, M, Newman, AH, Pope, S, Heales, SJR, Friberg, L, Law, I , Pinborg, LH, Sitte, HH, Loland, C, Shi, L, Weinstein, H, Galli, A, Hjermind, LE, Møller, LB & Gether, U 2014, 'Missense dopamine transporter mutations associate with adult parkinsonism and ADHD', The Journal of Clinical Investigation, vol. 124, no. 7, pp. 3107-20. https://doi.org/10.1172/JCI73778

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title = "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.",

author = "Hansen, {Freja H} and Tina Skj{\o}rringe and Saiqa Yasmeen and Arends, {Natascha V} and Sahai, {Michelle A} and Kevin Erreger and Andreassen, {Thorvald F} and Marion Holy and Hamilton, {Peter J} and Viruna Neergheen and Merete Karlsborg and Newman, {Amy H} and Simon Pope and Heales, {Simon J R} and Lars Friberg and Ian Law and Pinborg, {Lars H} and Sitte, {Harald H} and Claus Loland and Lei Shi and Harel Weinstein and Aurelio Galli and Hjermind, {Lena E} and M{\o}ller, {Lisbeth B} and Ulrik Gether",

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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

SN - 0021-9738

VL - 124

SP - 3107

EP - 3120

JO - The Journal of Clinical Investigation

JF - The Journal of Clinical Investigation

IS - 7

ER -

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

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