Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile Parkinsonism-dystonia

Department of Medical and Molecular Genetics, University of Birmingham School of Medicine, Institute of Biomedical Research, Birmingham, United Kingdom.
The Journal of clinical investigation (Impact Factor: 13.22). 07/2009; 119(6):1595-603. DOI: 10.1172/JCI39060
Source: PubMed


Genetic variants of the SLC6A3 gene that encodes the human dopamine transporter (DAT) have been linked to a variety of neuropsychiatric disorders, particularly attention deficit hyperactivity disorder. In addition, the homozygous Slc6a3 knockout mouse displays a hyperactivity phenotype. Here, we analyzed 2 unrelated consanguineous families with infantile parkinsonism-dystonia (IPD) syndrome and identified homozygous missense SLC6A3 mutations (p.L368Q and p.P395L) in both families. Functional studies demonstrated that both mutations were loss-of-function mutations that severely reduced levels of mature (85-kDa) DAT while having a differential effect on the apparent binding affinity of dopamine. Thus, in humans, loss-of-function SLC6A3 mutations that impair DAT-mediated dopamine transport activity are associated with an early-onset complex movement disorder. Identification of the molecular basis of IPD suggests SLC6A3 as a candidate susceptibility gene for other movement disorders associated with parkinsonism and/or dystonic features.

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    • "Yet such arguments need not be always valid, as there is a fundamental difference between life-long genetic loss of function (LOF) and the titrated, reversible pharmacological blockade of a protein. For instance, LOF mutations in the dopamine transporter SLC6A3 lead to early stage Parkinsonism disease (Kurian et al., 2009), but SLC6A3 is also a principal target of methlyphenidate and in the treatment of psychiatric disorders. Further, LOF mutations in SLC12A3 have been found associated with Gitelman's syndrome, characterized by low blood pressure, and SLC12A3 could be mechanistically linked to the action of thiazides that treat hypertension (Brinkman et al., 2006). "
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    • "Although the basal ganglia, including striatum, may be actively involved in regulating sleep–wake behavior (Lazarus et al., 2013), the main role of the dopaminergic neurons in the striatum is the regulation of motor activity. Indeed, Dat À/À mice display clear hyperactivity (Giros et al., 1996), and a DAT loss of function mutation in humans causes infantile Parkinsonism-Dystonia with slow movements, rigidity and rest tremor (Kurian et al., 2009). Although our data were obtained in a rather small number of healthy individuals and await independent replication, they may be in line with the clinical manifestation of this fatal mutation. "
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