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.
Original language | English |
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Pages (from-to) | 1595-603 |
Number of pages | 9 |
Journal | Journal of Clinical Investigation |
Volume | 119 |
Issue number | 6 |
DOIs | |
Publication status | Published - 26 May 2009 |
Keywords
- Amino Acid Sequence
- Animals
- Base Sequence
- Child
- Child, Preschool
- Chromosomes, Human, Pair 5/genetics
- Dopamine Plasma Membrane Transport Proteins/chemistry
- Dystonia/genetics
- Female
- Homozygote
- Humans
- Male
- Microsatellite Repeats/genetics
- Molecular Sequence Data
- Mutation/genetics
- Oligonucleotide Array Sequence Analysis
- Parkinsonian Disorders/genetics
- Pedigree
- Phenotype
- Sequence Alignment
- Sequence Homology, Amino Acid