Functional characterization of a de novo missense variant in the SLC6A3 gene originally identified in a simplex ASD case as part of a whole-exome sequencing study in 175 ASD parent-child trios (originally described by Neale et al. in a 2012 Nature report) showed that this variant (T356M) resulted in anomalous dopamine transporter function and hyperactivity when expressed in the DA neurons of Drosophila (Hamilton et al., 2013). A missense variant in this same gene (p.Ala559Val), previously identified in individuals with ADHD (Mazei-Robison et al., 2005) and bipolar disorder (Grunhage et al., 2000), was recently identified in two unrelated male ASD probands and shown to alter dopamine function and trafficking (Bowton et al., 2014).
Molecular Function
This gene encodes an amine transporter that terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals. Mutations in this gene are associated with Parkinsonism-dystonia infantile (PKDYS) [MIM:613135], while variation in the number of 40 bp tandem repeats in the 3'UTR of this gene is associated with idiopathic epilepsy, attention-deficit hyperactivity disorder, dependence on alcohol and cocaine, susceptibility to Parkinson disease and protection against nicotine dependence.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.
DAT knockout flies and flies expressing a human DAT ASD mutant in a knockout background exhibit increased locomotor activity and are insensitive to amphetamine in further increasing locomotion.
References
Type
Title
Author, Year
Primary
De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
dDAT knockout construct DAT^fmn is a null allele.
Allele Type: Knockout
Strain of Origin: Genetic Background: w^1118
ES Cell Line: Mutant ES Cell Line: Model Source: Bloomington Indiana
Model Type:
Genetic
Model Genotype:
Transgenic
Mutation:
Transgene with ASD human mutation T356M is expressed using a TH driver in a dDAT knockout background.
Allele Type: ASD LOF mutation
Strain of Origin: Genetic Background: w^1118
ES Cell Line: Mutant ES Cell Line: Model Source: Bloomington Indiana
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
DAT^fmn mutation was discovered on second chromosome when isogenized (Kume et al., 2005). DAT^fmn mutation was then backcrossed with w flies for seven generations to recombinationally separate it from other lesions.
Allele Type: Knockout
Strain of Origin: Genetic Background: Bloomington 6326
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
DAT^fmn mutation was discovered on second chromosome when isogenized (Kume et al., 2005). DAT^fmn mutation was then backcrossed with w flies for seven generations to recombinationally separate it from other lesions. Adult males were fed sucrose solution containing 1 mM of amphetamine.
Allele Type: Knockout
Strain of Origin: Genetic Background: Bloomington 6326
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Transgenic
Mutation:
hDAT-R/W transgene was cloned into pBI-UASC and constructs were injected into embryos.
Allele Type: Humanized LOF mutation
Strain of Origin: Genetic Background: Bloomington 6236
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Transgenic
Mutation:
hDAT-R/W transgene was cloned into pBI-UASC and constructs were injected into embryos. Adult males were fed sucrose solution containing 1 mM of amphetamine.
Allele Type: Humanized LOF mutation
Strain of Origin: Genetic Background: Bloomington 6236
ES Cell Line: Mutant ES Cell Line: Model Source:
Description: Knockout dDAT flies do not show a significant increase in locomotor activity in response to amphetamine, compared to vehicle control, this is in contrast to flies expressing wildtype hDAT that show a significant increase in locomotor activity in response to amphetamine.
Exp Paradigm: For the amphetamine-induced locomotion, males were starved for 6 h and then fed sucrose (5mM) containing either amphetamine (10mM) or vehicle.
Description: dDAT knockout flies show increased locomotor activity compared to flies expressing a transgenic wildtype human DAT
Exp Paradigm: Locomotion was recorded by beam breaks and analyzed using equipment/software
Description: Flies expressing a transgenic mutant human DAT do not show a significant increase in locomotor activity in response to amphetamine, compared to vehicle control, this is in contrast to flies expressing wildtype hDAT that show a significant increase in locomotor activity in response to amphetamine.
Exp Paradigm: For the amphetamine-induced locomotion, males were starved for 6 h and then fed sucrose (5mM) containing either amphetamine (10mM) or vehicle.
Description: Flies expressing a transgenic mutant human DAT show increased locomotor activity compared to flies expressing a transgenic wildtype human DAT
Exp Paradigm: Locomotion was recorded by beam breaks and analyzed using equipment/software
