The human gene SLC6A3 has been identified as a candidate susceptibility locus for attention deficit hyperactivity 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 autism (FBhh0000652).
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]
Attention-deficit/hyperactivity disorder (ADHD) is a chronic condition that includes a combination of persistent problems, such as difficulty sustaining attention, hyperactivity and impulsive behavior; the condition often continues into adulthood (https://www.mayoclinic.org/diseases-conditions/adhd/symptoms-causes/syc-20350889).
Meta-regression analyses have estimated the worldwide ADHD/HKD prevalence at between 5.3% and 7.1% in children and adolescents, and at 3.4% (range 1.2-7.3%) in adults (http://adhd-institute.com/burden-of-adhd/epidemiology/).
ADHD is the most common childhood-onset behavioral disorder, affecting approximately 5 to 10% of children and adolescents (Wolraich et al., 1996; pubmed: 8714320). In this condition, persistent inattention and/or hyperactive-impulsive behavior results in impaired social and/or academic functioning. Boys are affected about 8 times more frequently than girls (Zametkin et al., 1990; pubmed:2233902). [from MIM:143465; 2017.11.21]
Association of variants of SLC6A3 (DAT1) with ADHD has been shown in some studies, but has not been replicated in others (Thapar, et al, 2012; pubmed:21903599). ADHDgene (http://adhd.psych.ac.cn/) reports a large number of studies that have assessed association of ADHD with natural variants of the SLC6A3 gene, with both positive and negative results [caveat emptor: the ADHDgene database has not been updated since Feb. 2014].
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.
