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General Information
Name
autism spectrum disorder, susceptibility to (postulated), SLC6A3-related
FlyBase ID
FBhh0000652
OMIM
Overview

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]

Disease Summary Information
Parent Disease Summary: autism spectrum disorder, susceptibility to
Symptoms and phenotype
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 (OMIM: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 OMIM:209850; 2017.03.18]
Specific Disease Summary: autism spectrum disorder, susceptibility to (postulated), SLC6A3-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
Genetics
Cellular phenotype and pathology
Molecular information
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.
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to one: 2 human to 1 Drosophila; the human genes are SLC6A3 and SLC6A2; multiple less closely related genes exist in both species.
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to one: 2 human to 1 Drosophila; the human genes are SLC6A3 and SLC6A2; multiple less closely related genes exist in both species.
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    Dopamine transporter (DAT) encodes a dopamine transporter that mediates uptake of dopamine from the synaptic cleft. Its loss increases extracellular dopamine and is associated with behavioral phenotypes including increased activity and decreased sleep. [Date last reviewed: 2019-03-07]
    Gene Groups / Pathways
    Comments on ortholog(s)
    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.
    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (0 groups)
    Alleles Reported to Model Human Disease (Disease Ontology) (1 alleles)
    Models Based on Experimental Evidence ( 1 )
    Allele
    Disease
    Evidence
    References
    Modifiers Based on Experimental Evidence ( 0 )
    Allele
    Disease
    Interaction
    References
    Genetic Tools, Stocks and Reagents
    References (9)