Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Missense dopamine transporter mutations associate with adult parkinsonism and ADHD.
Hansen FH, Skjørringe T, Yasmeen S, Arends NV, Sahai MA, Erreger K, Andreassen TF, Holy M, Hamilton PJ, Neergheen V, Karlsborg M, Newman AH, Pope S, Heales SJ, Friberg L, Law I, Pinborg LH, Sitte HH, Loland C, Shi L, Weinstein H, Galli A, Hjermind LE, Møller LB, Gether U.
???displayArticle.abstract???
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.
Andersen,
Combined PET/MR imaging in neurology: MR-based attenuation correction implies a strong spatial bias when ignoring bone.
2014, Pubmed
Andersen,
Combined PET/MR imaging in neurology: MR-based attenuation correction implies a strong spatial bias when ignoring bone.
2014,
Pubmed Beuming,
A comprehensive structure-based alignment of prokaryotic and eukaryotic neurotransmitter/Na+ symporters (NSS) aids in the use of the LeuT structure to probe NSS structure and function.
2006,
Pubmed Beuming,
The binding sites for cocaine and dopamine in the dopamine transporter overlap.
2008,
Pubmed Bjerggaard,
Surface targeting of the dopamine transporter involves discrete epitopes in the distal C terminus but does not require canonical PDZ domain interactions.
2004,
Pubmed Blackstone,
Infantile parkinsonism-dystonia: a dopamine "transportopathy".
2009,
Pubmed Borghammer,
Cortical hypometabolism and hypoperfusion in Parkinson's disease is extensive: probably even at early disease stages.
2010,
Pubmed Bowton,
Dysregulation of dopamine transporters via dopamine D2 autoreceptors triggers anomalous dopamine efflux associated with attention-deficit hyperactivity disorder.
2010,
Pubmed Cha,
Rhodamine-labeled 2beta-carbomethoxy-3beta-(3,4-dichlorophenyl)tropane analogues as high-affinity fluorescent probes for the dopamine transporter.
2005,
Pubmed Claxton,
Ion/substrate-dependent conformational dynamics of a bacterial homolog of neurotransmitter:sodium symporters.
2010,
Pubmed Cook,
Association of attention-deficit disorder and the dopamine transporter gene.
1995,
Pubmed Crosiers,
Parkinson disease: insights in clinical, genetic and pathological features of monogenic disease subtypes.
2011,
Pubmed Cyr,
Sustained elevation of extracellular dopamine causes motor dysfunction and selective degeneration of striatal GABAergic neurons.
2003,
Pubmed Daniels,
Regulated trafficking of the human dopamine transporter. Clathrin-mediated internalization and lysosomal degradation in response to phorbol esters.
1999,
Pubmed Eriksen,
Visualization of dopamine transporter trafficking in live neurons by use of fluorescent cocaine analogs.
2009,
Pubmed Fog,
Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport.
2006,
Pubmed Franke,
The genetics of attention deficit/hyperactivity disorder in adults, a review.
2012,
Pubmed Fusar-Poli,
Striatal dopamine transporter alterations in ADHD: pathophysiology or adaptation to psychostimulants? A meta-analysis.
2012,
Pubmed Gainetdinov,
Strengths and limitations of genetic models of ADHD.
2010,
Pubmed Gainetdinov,
Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.
1999,
Pubmed Gainetdinov,
Monoamine transporters: from genes to behavior.
2003,
Pubmed Gainetdinov,
Dopamine transporter mutant mice in experimental neuropharmacology.
2008,
Pubmed Girard,
Schizophrenia genetics: putting all the pieces together.
2012,
Pubmed Gizer,
Candidate gene studies of ADHD: a meta-analytic review.
2009,
Pubmed Gowrishankar,
Good riddance to dopamine: roles for the dopamine transporter in synaptic function and dopamine-associated brain disorders.
2014,
Pubmed Gratten,
Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease.
2013,
Pubmed Grünhage,
Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1).
2000,
Pubmed Gu,
Stable expression of biogenic amine transporters reveals differences in inhibitor sensitivity, kinetics, and ion dependence.
1994,
Pubmed Günther,
ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells.
1998,
Pubmed Hamilton,
De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.
2013,
Pubmed Hastrup,
Symmetrical dimer of the human dopamine transporter revealed by cross-linking Cys-306 at the extracellular end of the sixth transmembrane segment.
2001,
Pubmed Holst,
PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance.
2013,
Pubmed Hyland,
Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population.
1993,
Pubmed Ingram,
Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons.
2002,
Pubmed Ishibashi,
Cerebrospinal fluid metabolite and nigrostriatal dopaminergic function in Parkinson's disease.
2010,
Pubmed Iversen,
Dopamine: 50 years in perspective.
2007,
Pubmed Jones,
Profound neuronal plasticity in response to inactivation of the dopamine transporter.
1998,
Pubmed Jones,
Loss of autoreceptor functions in mice lacking the dopamine transporter.
1999,
Pubmed Kantcheva,
Chloride binding site of neurotransmitter sodium symporters.
2013,
Pubmed Khoshbouei,
Amphetamine-induced dopamine efflux. A voltage-sensitive and intracellular Na+-dependent mechanism.
2003,
Pubmed Kiessling,
Domain coupling in asymmetric lipid bilayers.
2009,
Pubmed Krishnamurthy,
X-ray structures of LeuT in substrate-free outward-open and apo inward-open states.
2012,
Pubmed Kristensen,
SLC6 neurotransmitter transporters: structure, function, and regulation.
2011,
Pubmed Kurian,
Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: an observational cohort and experimental study.
2011,
Pubmed Kurian,
Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia.
2009,
Pubmed Kurian,
The monoamine neurotransmitter disorders: an expanding range of neurological syndromes.
2011,
Pubmed Leo,
Transgenic mouse models for ADHD.
2013,
Pubmed Loland,
Identification of intracellular residues in the dopamine transporter critical for regulation of transporter conformation and cocaine binding.
2004,
Pubmed Lunardi,
Correlation between changes in CSF dopamine turnover and development of dyskinesia in Parkinson's disease.
2009,
Pubmed Mazei-Robison,
Anomalous dopamine release associated with a human dopamine transporter coding variant.
2008,
Pubmed Mazei-Robison,
Sequence variation in the human dopamine transporter gene in children with attention deficit hyperactivity disorder.
2005,
Pubmed McElvain,
A multisubstrate mechanism of striatal dopamine uptake and its inhibition by cocaine.
1992,
Pubmed Meinild,
Zinc potentiates an uncoupled anion conductance associated with the dopamine transporter.
2004,
Pubmed
,
Xenbase Ng,
Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood.
2014,
Pubmed Penmatsa,
X-ray structure of dopamine transporter elucidates antidepressant mechanism.
2013,
Pubmed Penmatsa,
How LeuT shapes our understanding of the mechanisms of sodium-coupled neurotransmitter transporters.
2014,
Pubmed Phillips,
Scalable molecular dynamics with NAMD.
2005,
Pubmed Pitcher,
Reduced striatal volumes in Parkinson's disease: a magnetic resonance imaging study.
2012,
Pubmed Purper-Ouakil,
Neurobiology of attention deficit/hyperactivity disorder.
2011,
Pubmed Puschmann,
Monogenic Parkinson's disease and parkinsonism: clinical phenotypes and frequencies of known mutations.
2013,
Pubmed Qi,
Characterization of a CNS cell line, CAD, in which morphological differentiation is initiated by serum deprivation.
1997,
Pubmed Rasmussen,
A single nucleotide polymorphism in the human serotonin transporter introduces a new site for N-linked glycosylation.
2009,
Pubmed Rickhag,
A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter.
2013,
Pubmed Russell,
Overview of animal models of attention deficit hyperactivity disorder (ADHD).
2011,
Pubmed Sakrikar,
Attention deficit/hyperactivity disorder-derived coding variation in the dopamine transporter disrupts microdomain targeting and trafficking regulation.
2012,
Pubmed Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed Schmitt,
Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates.
2013,
Pubmed Shan,
The substrate-driven transition to an inward-facing conformation in the functional mechanism of the dopamine transporter.
2011,
Pubmed Shi,
The mechanism of a neurotransmitter:sodium symporter--inward release of Na+ and substrate is triggered by substrate in a second binding site.
2008,
Pubmed Sitte,
Carrier-mediated release, transport rates, and charge transfer induced by amphetamine, tyramine, and dopamine in mammalian cells transfected with the human dopamine transporter.
1998,
Pubmed Sonders,
Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants.
1997,
Pubmed
,
Xenbase Sotnikova,
Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease.
2005,
Pubmed Sotnikova,
Molecular biology, pharmacology and functional role of the plasma membrane dopamine transporter.
2006,
Pubmed Stys,
General mechanisms of axonal damage and its prevention.
2005,
Pubmed Sulzer,
How addictive drugs disrupt presynaptic dopamine neurotransmission.
2011,
Pubmed Sulzer,
Mechanisms of neurotransmitter release by amphetamines: a review.
2005,
Pubmed Torres,
Plasma membrane monoamine transporters: structure, regulation and function.
2003,
Pubmed Veltman,
De novo mutations in human genetic disease.
2012,
Pubmed Yu,
The Role of Intracellular Sodium in the Regulation of NMDA-Receptor-Mediated Channel Activity and Toxicity.
2006,
Pubmed Zhao,
Ion-controlled conformational dynamics in the outward-open transition from an occluded state of LeuT.
2012,
Pubmed Zhuang,
Hyperactivity and impaired response habituation in hyperdopaminergic mice.
2001,
Pubmed Zomot,
Mechanism of chloride interaction with neurotransmitter:sodium symporters.
2007,
Pubmed
