Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia
Open Access
- 26 May 2009
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 119 (6), 1595-1603
- https://doi.org/10.1172/JCI39060
Abstract
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.Keywords
This publication has 24 references indexed in Scilit:
- Anomalous Dopamine Release Associated with a Human Dopamine Transporter Coding VariantJournal of Neuroscience, 2008
- The Mechanism of a Neurotransmitter:Sodium Symporter—Inward Release of Na+ and Substrate Is Triggered by Substrate in a Second Binding SiteMolecular Cell, 2008
- Substrates dissociate dopamine transporter oligomersJournal of Neurochemistry, 2007
- Substrates and inhibitors display different sensitivity to expression level of the dopamine transporter in heterologously expressing cellsJournal of Neurochemistry, 2006
- Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transportersNature, 2005
- Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degenerationJournal of Neural Transmission, 2004
- Mutations in the Na+/K+-ATPase α3 Gene ATP1A3 Are Associated with Rapid-Onset Dystonia ParkinsonismNeuron, 2004
- The Role of N-Glycosylation in Function and Surface Trafficking of the Human Dopamine TransporterPublished by Elsevier BV ,2004
- Aspartate 345 of the Dopamine Transporter Is Critical for Conformational Changes in Substrate Translocation and Cocaine BindingPublished by Elsevier BV ,2004
- Evidence for Distinct Sodium-, Dopamine-, and Cocaine-dependent Conformational Changes in Transmembrane Segments 7 and 8 of the Dopamine TransporterPublished by Elsevier BV ,2003