The human gene SLC6A3 has been identified as a candidate susceptibility locus for autism spectrum disorder. SLC6A3 encodes a dopamine transporter that effects reuptake of the neurotransmitter at presynaptic terminals (a sodium:neurotransmitter symporter). There is a single orthologous dopamine transporter in Drosophila, Dmel\DAT, for which classical loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\DAT is also orthologous to second gene in human, SLC6A2, which acts as a sodium:neurotransmitter symporter for norepinephrine in human. SLC6A3 is also implicated in infantile parkinsonism-dystonia (see FBhh0000749) and is postulated to be a susceptibility locus for development of ADHD (see FBhh0000654).
Multiple different UAS constructs of the human Hsap\SLC6A3 have been introduced into flies, including wild-type SLC6A3 and a gene carrying a mutational lesion implicated in autism spectrum disorder. Variant(s) implicated in human disease tested (as transgenic human gene, SLC6A3): the T356M and ΔN336 variant forms have been introduced into flies. Heterologous rescue (functional complementation) is observed: expression of wild-type SLC6A3 in dopaminergic neurons is able to rescue the hyperactive phenotype of a Dmel\DAT loss-of-function allele; expression of the T356M variant form of SLC6A3 also reduces the hyperactive phenotype, but to a significantly lesser extent. Using flies homozygous for a Dmel\DAT loss-of-function mutation, phenotypes of the ΔN336 Hsap\SLC6A3 variant, including dopamine uptake in the brain and various behavioral phenotypes, have been compared with those of the wild-type human gene.
Phenotypes of the original loss-of-function mutation of Dmel\DAT (DATfmn) include hyperactivity, sleep-defective phenotypes and locomotor-behavior-defective phenotypes. These phenotypes are relevant to modela of both autism and ADHD. Pan-neuronal knockdown of DAT, effected by RNAi, results in hyperactivity and sleep loss; the phenotypes are more pronounced during night. Feeding with the ADHD-ameliorating pharmaceutical MPH (methylphenidate) results in reduction of the hyperactivity and sleep phenotypes.
[updated May 2019 by FlyBase; FBrf0222196]
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996, pubmed:8655659; Risch et al., 1999, pubmed:10417292). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (MIM:608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008; pubmed:18698615). [from MIM:209850; 2017.03.18]
The SFARI Gene autism database ( https:gene.sfari.org ) rates the gene-autism association for SLC6A3 as strong candidate (score 2). [2020.11.05]
A family of integral membrane proteins, multiple members of the solute carrier family 6 (SLC6) are amine transporters that terminate the action of specific amine neurotransmitters by high affinity sodium-dependent reuptake into presynaptic terminals (described as sodium:neurotransmitter symporters). SLC6A3 is a dopamine transporter (DAT) and is widely distributed throughout the brain in areas of dopaminergic activity, including the striatum and substantia nigra.
Many to one: 2 human to 1 Drosophila; the human genes are SLC6A3 and SLC6A2; multiple less closely related genes exist in both species.
Many to one: 2 human to 1 Drosophila; the human genes are SLC6A3 and SLC6A2; multiple less closely related genes exist in both species.
Moderate- to high-scoring ortholog of human SLC6A3 (human dopamine transporter) and SLC6A2 (human norepinephrine transporter) (1 Drosophila to 2 human); multiple less closely related genes exist in both species. Dmel\DAT shares 52-56% identity and 68-72% similarity with human SLC6A2 and SLC6A3.
