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: 13.77). 07/2009; 119(6):1595-603. DOI: 10.1172/JCI39060
Source: PubMed

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.

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Available from: Paul Gissen, Aug 17, 2015
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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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    ABSTRACT: Accumulating evidence suggests that dopamine plays a key role in sleep-wake regulation. Cerebral dopamine levels are regulated primarily by the dopamine transporter (DAT) in the striatum and by catechol-O-methyl-transferase (COMT) in the prefrontal cortex. We hypothesized that the variable-number-tandem-repeat (VNTR) polymorphism in the 3'-untranslated region of the gene encoding DAT (DAT1, SLC6A3; rs28363170) and the Val158Met polymorphism of COMT (rs4680) differently affect actigraphy-derived rest-activity cycles and sleep estimates in healthy adults (65 men; 45 women; age range: 19-35 years). Daytime sleepiness, continuous rest-actigraphy and sleep diary data during roughly 4-weeks were analyzed. Nine-repeat (9R) allele carriers of DAT1 (n = 48) more often reported elevated sleepiness (Epworth sleepiness score ≥10) than 10-repeat (10R) allele homozygotes (n = 62, p < 0.02). Moreover, male 9R allele carriers showed higher wrist activity, whereas this difference was not present in women ("DAT1 genotype" × "gender" interaction: p < 0.005). Rest-activity patterns did not differ among COMT genotypes. Nevertheless, a significant "COMT genotype" × "type of day" (workdays vs. rest days) interaction for sleep duration was observed (p = 0.04). The Val/Val (n = 36) and Met/Met (n = 24) homozygotes habitually prolonged sleep on rest days compared to workdays by more than 30 min, while Val/Met heterozygotes (n = 50) did not significantly extend their sleep (mean difference: 7 min). Moreover, whereas the proportion of women among the genotype groups did not differ, COMT genotype affected body-mass-index (BMI), such that Val/Met individuals had lower BMI than the homozygous genotypes (p < 0.04). While awaiting independent replication and confirmation, our data support an association of genetically-determined differences in cerebral dopaminergic neurotransmission with daytime sleepiness and individual rest-activity profiles, as well as other sleep-associated health characteristics such as the regulation of BMI. The differential associations of DAT1 and COMT polymorphisms may reflect the distinct local expression of the encoded proteins in the brain.
    Chronobiology International 03/2014; 31(5)(5). DOI:10.3109/07420528.2014.896376 · 2.88 Impact Factor
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    • "As reported in this study and by our group previously, the majority of infantile cases the mutant human DAT retain 0–5% residual DAT activity whereas the human DAT mutants Ala314Val (atypical juvenile DTDS cases) retain higher residual dopamine. Furthermore human DAT mutants of atypical juvenile DTDS cases demonstrate some residual and even up to normal levels of expression of mature transporter protein at the cell surface (Henriksen et al., 2012), whereas surface expression of mature DAT in classical infantile-onset DTDS is severely reduced or absent (Kurian et al., 2009, 2011a). These atypical juvenile and adult DTDS (Henriksen et al., 2012) cases provide insight into potential genotype–phenotype correlations in DTDS and suggest that different SLC6A3 genotypes may therefore have a differential impact on DAT dysfunction. "
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    ABSTRACT: Dopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine 'transportopathy' to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5-34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having 'juvenile parkinsonism'. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more severely impacted in dopamine transporter mutants causing infantile-onset rather than juvenile-onset disease. Dopamine transporter mutants also showed diminished dopamine binding affinity, reduced cell surface transporter, loss of post-translational dopamine transporter glycosylation and failure of amphetamine-mediated dopamine efflux. Our data series expands the clinical phenotypic continuum of dopamine transporter deficiency syndrome and indicates that there is a phenotypic spectrum from infancy (early onset, rapidly progressive disease) to childhood/adolescence and adulthood (later onset, slower disease progression). Genotype-phenotype analysis in this cohort suggests that higher residual dopamine transporter activity is likely to contribute to postponing disease presentation in these later-onset adult cases. Dopamine transporter deficiency syndrome remains under-recognized and our data highlights that dopamine transporter deficiency syndrome should be considered as a differential diagnosis for both infantile- and juvenile-onset movement disorders, including cerebral palsy and juvenile parkinsonism.
    Brain 03/2014; 137(4). DOI:10.1093/brain/awu022 · 10.23 Impact Factor
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    • "Although DAT plays a significant role in normal DA signaling, is a prominent drug target, and has been repeatedly implicated by genetic association studies in disorders such as ADHD, only limited efforts have sought evidence for functional coding variation associated with the DAT gene (SLC6A3) that could contribute to ADHD risk. Thus far, several studies have sought evidence for SLC6A3 coding polymorphisms, identifying multiple subjects both heterozygous (Cargill et al., 1999; Grünhage et al., 2000; Hamilton et al., 2013; Mazei-Robison et al., 2005; Mergy MA and Blakely RD, unpublished data; Puffenberger et al., 2012; Sakrikar et al., 2012; Vandenbergh et al., 2000), and homozygous (Kurian et al., 2009, 2011) for nonsynonymous variants. Screening of ADHD subjects for new DAT coding variants is also ongoing in various diseases including bipolar disorder and autism with comorbid ADHD (Davis and Kollins, 2012; Mahajan et al., 2012; Rommelse et al., 2011). "
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    ABSTRACT: Alterations in dopamine (DA) signaling underlie the most widely held theories of molecular and circuit level perturbations that lead to risk for attention-deficit hyperactivity disorder (ADHD). The DA transporter (DAT), a presynaptic reuptake protein whose activity provides critical support for DA signaling by limiting DA action at pre- and postsynaptic receptors, has been consistently associated with ADHD through pharmacological, behavioral, brain imaging and genetic studies. Currently, the animal models of ADHD exhibit significant limitations, stemming in large part from their lack of construct validity. To remedy this situation, we have pursued an effort to create a mouse model derived from functional nonsynonymous variation in the DAT gene (SLC6A3) of ADHD probands. We trace our path from the identification of these variants to in vitro biochemical and physiological studies to the production of the DAT Val559 mouse model. We discuss our initial findings with these animals and their promise in the context of existing rodent models of ADHD.
    Neurochemistry International 12/2013; 73. DOI:10.1016/j.neuint.2013.11.009 · 2.65 Impact Factor
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