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 re-uptake 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 a required for substrate efflux. In Drosophila melanogaster, 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.

Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies

“…Some evidence suggests that DA is involved in mediating some of the same maternal behaviours that are exhibited under the influence of OXT 93,94 as well as pair bonding. [95][96][97][98] Furthermore, OXT has been implicated in helping to mediate addiction and withdrawal in the mesolimbic dopaminergic pathways, 99 and differences in peripheral and central levels of OXT have been found in patients with disorders with potential DA abnormalities, such as autism, [100][101][102][103] schizophrenia [104][105][106][107][108] and social anxiety disorder. [109][110][111][112] In addition, preclinical studies have shown that dopaminergic fibres may regulate OXT release 113,114 and that the receptor binding sites and neuronal fibres of both of these neurochemicals reside in the same regions of the central nervous system and are often next to each other.…”

Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances – The case of the benzofuran 5-MAPB

“…We present here, on the basis of the crystal structure from Drosophila melanogaster dopamine transporter (dDAT) (PDB ID: 4XP1) (Wang et al, 2015), a molecular model of 5-MAPB bound to rat DAT (rDAT), in comparison with that of dopamine, amphetamine, 5-APB, MDMA, cocaine and RTI-121 also bound to rDAT. Our studies compare the structural changes produced by various ligands binding to rDAT to the already ongoing work in hDAT models (Hamilton et al, 2013;Hansen et al, 2014;Khelashvili et al, 2015aKhelashvili et al, , 2015b since it is the primary animal model used in functional studies and pre-clinical drug abuse testing.…”

“…The construction of the homology model of rDAT (rDAT dDAT ) in complex with dopamine uses established protocols previously described for the construction of a human DAT (hDAT) model (Hamilton et al, 2013;Hansen et al, 2014;Khelashvili et al, 2015aKhelashvili et al, , 2015b. Briefly, as the template, the homology model uses the recent crystal structure of the neurotransmitter sodium symporter (NSS) DAT from Drosophila melanogaster (dDAT) bound to dopamine (PDB ID: 4XP1) (Wang et al, 2015).…”

Glyphosate, pathways to modern diseases IV: cancer and related pathologies

“…One possibility is that increased demand for melanin in the skin depletes the supply of tyrosine for dopamine synthesis. Genetic mutations in dopamine transport proteins have been linked to autism [195,196]. The defect features a persistent reverse transport of dopamine (substrate efflux from the synapse), which reduces the amount of time extracellular dopamine is available for signalling effects [195].…”

“…Genetic mutations in dopamine transport proteins have been linked to autism [195,196]. The defect features a persistent reverse transport of dopamine (substrate efflux from the synapse), which reduces the amount of time extracellular dopamine is available for signalling effects [195]. Other genes of the dopaminergic network are also linked to autism, including syntaxin [197] and enzymes involved in dopamine metabolism [198].…”