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

Abstract

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.

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Acknowledgements

We gratefully acknowledge investigators in the NIH ARRA Autism Sequencing Consortium: MJ Daly, RA Gibbs, E Boerwinkle, JD Buxbaum, EH Cook, B Devlin, ET Lim, BM Neale, K Roeder, A Sabo, GD Schellenberg, C Stevens and JS Sutcliffe; and programmatic support and contribution to the AASC project by T Lehner (NIMH), P Bender (NIMH) and A Felsenfeld (NHGRI). This work was supported by NSF Graduate Research Fellowship DGE0909667 and F31 DA 035535-01 (PJH), U54-GM087519 (SS and HSM), P50 HD055751 (EHC), DA13975 and P01 DA12408 (AG and UG), and MH089482 (JSS).

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Hamilton, P., Campbell, N., Sharma, S. et al. De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder. Mol Psychiatry 18, 1315–1323 (2013). https://doi.org/10.1038/mp.2013.102

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