Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

• Published in: The Journal of clinical investigation Vol. 124; no. 7; pp. 3107 - 3120
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2014
• Subjects: Adult; Amino Acid Sequence; Amino Acid Substitution; Animals; Attention Deficit Disorder with Hyperactivity - complications; Attention Deficit Disorder with Hyperactivity - genetics; Attention Deficit Disorder with Hyperactivity - metabolism; Attention deficit hyperactivity disorder; Autism; Biomedical research; Brain - diagnostic imaging; Brain - metabolism; Cohort Studies; Development and progression; DNA Mutational Analysis; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins - chemistry; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine Plasma Membrane Transport Proteins - metabolism; Female; Genetic aspects; Genetic variation; HEK293 Cells; Humans; Identification and classification; Male; Medical research; Membrane proteins; Models, Molecular; Molecular Sequence Data; Mutant Proteins - chemistry; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Mutation, Missense; Oocytes - metabolism; Parkinson's disease; Parkinsonian Disorders - complications; Parkinsonian Disorders - genetics; Parkinsonian Disorders - metabolism; Pedigree; Positron-Emission Tomography; Protein Conformation; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Sequence Homology, Amino Acid; Sodium - metabolism; Tomography, Emission-Computed, Single-Photon; Xenopus
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI73778

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.