De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder

Molecular Psychiatry (Impact Factor: 14.5). 08/2013; 18(12). DOI: 10.1038/mp.2013.102


De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution at site 356 (hDAT T356M). The dopamine transporter (DAT) is a presynaptic membrane protein that regulates dopaminergic tone in the central nervous system by mediating the high-affinity reuptake of synaptically released DA, making it a crucial regulator of DA homeostasis. Here, we report the first functional, structural and behavioral characterization of an ASD-associated de novo mutation in the hDAT. We demonstrate that the hDAT T356M displays anomalous function, characterized as a persistent reverse transport of DA (substrate efflux). Importantly, in the bacterial homolog leucine transporter, substitution of A289 (the homologous site to T356) with a Met promotes an outward-facing conformation upon substrate binding. In the substrate-bound state, an outward-facing transporter conformation is required for substrate efflux. In Drosophila melanogaster, the expression of hDAT T356M in DA neurons-lacking Drosophila DAT leads to hyperlocomotion, a trait associated with DA dysfunction and ASD. Taken together, our findings demonstrate that alterations in DA homeostasis, mediated by aberrant DAT function, may confer risk for ASD and related neuropsychiatric conditions. Molecular Psychiatry advance online publication, 27 August 2013; doi:10.1038/mp.2013.102

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Available from: Heinrich J G Matthies
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    • "Genetic factors that are shared between both traits might be involved in dopamine functions , so genetic mechanisms involved in dopaminergic pathways , such as the SLC6A3 gene , might be interesting to explore [ Hamilton et al . , 2013 ; Neale et al . , 2012 ; Norbury and Husain , 2015 ] . This study has several limitations . First , we assessed ASD traits and ES based on self - reports only . Although this approach is common in epidemiological research , multiple ASD and ES measurements would reinforce the validity of our findings . Second , the twin - sibling sample"
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    • "Regarding the 0166-4328/© 2015 Elsevier B.V. All rights reserved. dopamine (DA) system, genetic studies have reported that mutations of DA-associated genes—such as the DA transporter [3], DA receptors [4] [5] [6] [7], and enzymes of DA synthesis [8]—were related to ASD. Furthermore, positron emission tomography demonstrated that the DA transporter binding was significantly higher in the orbitofrontal cortex of high-functioning autistic adults compared with controls [9]. "
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    • "FMR1 has been strongly implicated in ASD, and its interactor CYFIP1 also plays a role in ASD pathogenesis (Bozdagi et al., 2012; Leblond et al., 2012) DAT: Encodes the dopamine transporter (DAT), a presynaptic membrane protein that regulates dopaminergic tone by the high-affinity reuptake of synaptically released dopamine. DAT has been associated with ASD (Hamilton et al., 2013) DNM2: Encodes dynamin II, a cytoskeletal protein associated with microtubules; interacts with D2 receptors. While DNM2 has not been associated with ASD, it interacts with SRC (see further) and SHANK genes, which are implicated in autism. "
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