Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood

Ng, Joanne; Zhen, Juan; Meyer, Esther; Erreger, Kevin; Li, Yan; Kakar, Naseebullah; Ahmad, Jamil; Thiele, Holger; Kubisch, Christian; Rider, Nicholas L.; Morton, D. Holmes; Strauss, Kevin A.; Puffenberger, Erik G.; D’Agnano, Daniela; Anikster, Yair; Carducci, Claudia; Hyland, Keith; Rotstein, Michael; Leuzzi, Vincenzo; Borck, Guntram; Reith, Maarten E. A.; Kurian, Manju A.

doi:10.1093/brain/awu022

Cited by 140 publications

(216 citation statements)

References 35 publications

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“…DAT deficiency syndrome was recently described as an autosomal recessively inherited disease, manifesting in childhood, typically early infancy, with parkinsonism-dystonia (14,15,48). Mutations in SLC6A3 that probably lead to ER retention of the encoded DAT proteins were identified as the cause of disease.…”

Section: Discussionmentioning

confidence: 99%

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

Herborg

Skjørringe²,

Yasmeen³

et al. 2014

J. Clin. Invest.

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133

171

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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.

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Section: Discussionmentioning

confidence: 99%

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

Herborg

Skjørringe²,

Yasmeen³

et al. 2014

J. Clin. Invest.

Self Cite

133

171

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“…For instance, the impact of DAT genetic variation on behavioral changes underlying mental illness stems from pioneering studies of the DAT knockout mouse, which demonstrated that genetic elimination of DAT expression reduces presynaptic DA stores, elevates extracellular DA, and produces hyperactivity in a novel environment (Giros et al, 1996). However, humans that are homozygous for loss-offunction DAT (SLC6A3) alleles present with a complex disorder that resembles PD, rather than ADHD (see section V.B; Kurian et al, 2011;Ng et al, 2014). Instead, clinical studies that genetically screen individuals with ADHD, as well as preclinical studies using cell lines and genetic mouse models, have suggested that variations in the genes encoding for DAT, rather than simple loss of function, and/or DA receptors are associated with risk for ADHD (Gill et al, 1997;Bobb et al, 2005;Mazei-Robison et al, 2005;Sakrikar et al, 2012;Mergy et al, 2014).…”

Section: Dopamine Transporter Vesicular Monoaminementioning

confidence: 99%

“…In addition, loss-of-function mutations of the human SLC6A3 gene that encodes DAT have been linked to infantile parkinsonism-dystonia (also known as DAT deficiency syndrome; Kurian et al, 2009Kurian et al, , 2011, which is a severe neurologic syndrome that usually presents in early infancy with hypokinetic parkinsonism (Assmann et al, 2004). Of note, recent studies have shown evidence that DAT missense mutations can also lead to later-onset DAT deficiency syndrome and parkinsonism in adolescents and adults (Hansen et al, 2014;Ng et al, 2014). Decreases in VMAT2 within the striatal brain regions as assessed by [ 11 C]dihydrotetrabenazine (DHTBZ) binding have also been reported in patients with PD (de la Fuente-Fernández et al, 2011).…”

Section: Dopamine Transporter Vesicular Monoaminementioning

confidence: 99%

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

et al. 2015

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“…Further to this point, humans bearing homozygous, loss-offunction DAT mutations as seen in the DAT KO model, present with a complex disorder that, in juvenile stages, resembles Parkinson's disease (40,41). These findings suggest that DAT contributions to disorders such as ADHD and BPD may derive from less severe or qualitatively distinct changes in DAT activity than simple loss of function.…”

mentioning

confidence: 95%

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

Mergy¹,

Gowrishankar²,

Gresch

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

113

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Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPHevoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.T he neurotransmitter dopamine (DA) plays a key role in regulating brain circuits that control reward, attention, and locomotor activity (1-3), Accordingly, dopaminergic dysfunction is believed to contribute to several neuropsychiatric disorders including Parkinson's disease (4), bipolar disorder (BPD) (5), drug abuse and addiction (6), and attention-deficit hyperactivity disorder (ADHD) (7,8). The presynaptic DA transporter (DAT) is the primary mechanism for terminating DA signaling at the synapse (9) and is the primary target for several psychostimulant drugs including cocaine (COC), methylphenidate (MPH), and amphetamine (AMPH). COC and MPH are DAT antagonists, elevating extracellular DA levels by preventing DAT-mediated DA reuptake (10). AMPH actions are more complex (11). AMPH is structurally similar to DA and, as a result, is transported by DAT, competing with DA during the reuptake process. AMPH also induces DAT-mediated nonvesicular release, also termed "DA efflux," a process that involves the actions of intracellular signaling proteins such as CamKIIα (12-16) and , alterations in interactions with DAT-associated proteins and phospholipids (12,14,20), and changes in DAT phosphorylation (12,16,(21)(22)(23)) that biases the transporter toward an efflux-competent mechanism. Despite their mechanistic differences, MPH and AMPH both rapidly elevate DA in the CNS and are components of the most frequently prescribed medications for ADHD, Ritalin and Adderall, respectively. The DA modulatory actions of MPH and AMPH reinforce hypotheses derived from brain imaging studies (24) and the analysis of common genetic variation (25-30)...

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Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood

Cited by 140 publications

References 35 publications

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

Missense dopamine transporter mutations associate with adult parkinsonism and ADHD

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

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