Dysfunctional dopaminergic signaling underlies several neurological disorders and syndromes, including attention deficit hyperactivity disorder (ADHD), autism, schizophrenia, and parkinsonism. The sodium-coupled dopamine transporter (DAT) is known to regulate dopamine homeostasis, and mutations in SLC6A3, which encodes DAT, have been identified in individuals with movement disorders and psychiatric patients. Freja Hansen, Tina Skjørringe and colleagues at University of Copenhagen and Copenhagen University Hospital, respectively, evaluated a patient with both early-onset parkinsonism and ADHD that was heterozygous for 2 SLC6A3 missense mutations. There was no history of movement disorder or psychiatric disease in the patient’s family; however, the patient’s unaffected sister was heterozygous for one of the mutations (DAT-Ile312Phe), suggesting that the second mutation (DAT- Asp421Asn) was acquired de novo and contributed to disease onset. Both DAT-Ile312Phe and DAT-Asp421Asn targeted to the cell membrane, but exhibited reduced dopamine transport. DAT-Asp421Asn dysfunction was linked to compromised sodium binding capacity, and DAT-Asp421Asn-expressing cells exhibited an unexpected efflux of dopamine and a cation leak with the potential to further disturb dopaminergic signaling. This study links DAT missense mutations with early-onset parkinsonism in adults and correlates different dopaminergic pathologies with DAT dysfunction. The accompanying image shows single-photon emission computed tomography (SPECT) of [123I]FP-CIT binding to DAT in the brain of a healthy control patient (left) and in the patient characterized in this study at age 34 (middle) and 43 (right).
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.
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