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.
authors.forename: Freja H
authors.initials: FH
authors.lastname: Hansen
authors.forename: Tina
authors.initials: T
authors.lastname: Skjørringe
authors.forename: Saiqa
authors.initials: S
authors.lastname: Yasmeen
authors.forename: Natascha V
authors.initials: NV
authors.lastname: Arends
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Sahai
authors.forename: Kevin
authors.initials: K
authors.lastname: Erreger
authors.forename: Thorvald F
authors.initials: TF
authors.lastname: Andreassen
authors.forename: Marion
authors.initials: M
authors.lastname: Holy
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hamilton
authors.forename: Viruna
authors.initials: V
authors.lastname: Neergheen
authors.forename: Merete
authors.initials: M
authors.lastname: Karlsborg
authors.forename: Amy H
authors.initials: AH
authors.lastname: Newman
authors.forename: Simon
authors.initials: S
authors.lastname: Pope
authors.forename: Simon J R
authors.initials: SJ
authors.lastname: Heales
authors.forename: Lars
authors.initials: L
authors.lastname: Friberg
authors.forename: Ian
authors.initials: I
authors.lastname: Law
authors.forename: Lars H
authors.initials: LH
authors.lastname: Pinborg
authors.forename: Harald H
authors.initials: HH
authors.lastname: Sitte
authors.forename: Claus
authors.initials: C
authors.lastname: Loland
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
authors.forename: Aurelio
authors.initials: A
authors.lastname: Galli
authors.forename: Lena E
authors.initials: LE
authors.lastname: Hjermind
authors.forename: Lisbeth B
authors.initials: LB
authors.lastname: Møller
authors.forename: Ulrik
authors.initials: U
authors.lastname: Gether
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D009865:Oocytes / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D049268:Positron-Emission Tomography; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012964:Sodium / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon; D014981:Xenopus
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D050505:Mutant Proteins; D011994:Recombinant Proteins; D012964:Sodium; D004298:Dopamine