Human Gene Module / Chromosome 5 / SLC6A3

SLC6A3Solute carrier family 6 (neurotransmitter transporter), member 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 16
Rare Variants / Common Variants
11 / 3
Aliases
SLC6A3, DAT,  DAT1,  PKDYS
Associated Syndromes
-
Chromosome Band
5p15.33
Associated Disorders
-
Relevance to Autism

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
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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Mouse
Entrez GeneMouse Genome Informatics
Rat
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Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SLC6A3 (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1) Grnhage F , et al. (2000) No -
2 Positive Association Variation of the genes encoding the human glutamate EAAT2, serotonin and dopamine transporters and Susceptibility to idiopathic generalized epilepsy Sander T , et al. (2000) No -
3 Support Sequence variation in the human dopamine transporter gene in children with attention deficit hyperactivity disorder Mazei-Robison MS , et al. (2005) No -
4 Support Anomalous dopamine release associated with a human dopamine transporter coding variant Mazei-Robison MS , et al. (2008) No -
5 Support Attention deficit/hyperactivity disorder-derived coding variation in the dopamine transporter disrupts microdomain targeting and trafficking regulation Sakrikar D , et al. (2012) No -
6 Primary De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder Hamilton PJ , et al. (2013) Yes -
7 Support Missense dopamine transporter mutations associate with adult parkinsonism and ADHD Hansen FH , et al. (2014) No -
8 Recent Recommendation SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking Bowton E , et al. (2014) Yes -
9 Recent Recommendation The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants Mergy MA , et al. (2014) No -
10 Support Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (hDAT R51W) in dopamine neurotransmission and behaviors Cartier E , et al. (2015) Yes -
11 Recent Recommendation Neuropsychiatric disease-associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes Herborg F , et al. (2018) No -
12 Support Structural, functional, and behavioral insights of dopamine dysfunction revealed by a deletion in SLC6A3 Campbell NG , et al. (2019) Yes -
13 Recent Recommendation Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors DiCarlo GE , et al. (2019) Yes -
14 Support - Mir A et al. (2021) No -
15 Highly Cited Association of attention-deficit disorder and the dopamine transporter gene Cook EH Jr , et al. (1995) No -
16 Positive Association Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism Gill M , et al. (1997) No -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.*163A>G - missense_variant Familial Maternal Simplex 22514303 Sakrikar D , et al. (2012)
c.1261G>A p.Asp421Asn missense_variant Unknown - Simplex 24911152 Hansen FH , et al. (2014)
- p.Asn336del inframe_deletion Familial Paternal Simplex 30755521 Campbell NG , et al. (2019)
c.1067C>T p.Thr356Met missense_variant De novo - Simplex 23979605 Hamilton PJ , et al. (2013)
c.1078_1080del p.Ser360del inframe_deletion Familial Both parents - 34797406 Mir A et al. (2021)
c.1676C>T p.Ala559Val missense_variant Familial Maternal Simplex 25313507 Bowton E , et al. (2014)
c.1805A>G p.Glu602Gly missense_variant Familial Paternal Simplex 10889530 Grnhage F , et al. (2000)
c.151C>T p.Arg51Trp missense_variant Familial Maternal Multiplex 25774383 Cartier E , et al. (2015)
c.934A>T p.Ile312Phe missense_variant Unknown Not maternal Simplex 24911152 Hansen FH , et al. (2014)
c.1676C>T p.Ala559Val missense_variant Familial Maternal Multiplex 16171832 Mazei-Robison MS , et al. (2005)
c.1676C>T p.Ala559Val missense_variant Unknown Not maternal Multi-generational 10889530 Grnhage F , et al. (2000)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- 3'UTR microsatellite, 3_prime_UTR_variant - - - 9246671 Gill M , et al. (1997)
- 3'UTR microsatellite, 3_prime_UTR_variant - - - 7717410 Cook EH Jr , et al. (1995)
- 3'UTR microsatellite, 3_prime_UTR_variant - - - 10924870 Sander T , et al. (2000)
SFARI Gene score
2

Strong Candidate

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 in PMID 22495311) showed that this variant (T356M) resulted in anomalous dopamine transporter function and hyperactivity when expressed in the DA neurons of Drosophila (PMID 23979605). A missense variant in this same gene (p.Ala559Val), which had been previously identified in individuals with ADHD (PMID 16171832) and bipolar disorder (PMID 10889530), was observed in two unrelated male ASD probands (PMID 25313507). The p.Ala559Val variant has been experimentally shown to alter dopamine function and trafficking (PMIDs 18614672, 25313507). Campbell et al., 2019 characterized an in-frame deletion variant in the SLC6A3 gene (p.Asn336del) identified in an ASD proband from the Simons Simplex Collection, which had been inherited from a father with a broad autism phenotype, and demonstrated that this variant resulted in impaired dopamine transporter function in transfected cells and isolated Drosophila brain, as well as hyper-locomotion, increased grooming behavior, increased freezing following an audible fear stimulus, and impaired social interactions in flies.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

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 in PMID 22495311) showed that this variant (T356M) resulted in anomalous dopamine transporter function and hyperactivity when expressed in the DA neurons of Drosophila (PMID 23979605). A missense variant in this same gene (p.Ala559Val), which had been previously identified in individuals with ADHD (PMID 16171832) and bipolar disorder (PMID 10889530), was observed in two unrelated male ASD probands (PMID 25313507). The p.Ala559Val variant has been experimentally shown to alter dopamine function and trafficking (PMIDs 18614672, 25313507). Campbell et al., 2019 characterized an in-frame deletion variant in the SLC6A3 gene (p.Asn336del) identified in an ASD proband from the Simons Simplex Collection, which had been inherited from a father with a broad autism phenotype, and demonstrated that this variant resulted in impaired dopamine transporter function in transfected cells and isolated Drosophila brain, as well as hyper-locomotion, increased grooming behavior, increased freezing following an audible fear stimulus, and impaired social interactions in flies.

Reports Added
[New Scoring Scheme]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

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 in PMID 22495311) showed that this variant (T356M) resulted in anomalous dopamine transporter function and hyperactivity when expressed in the DA neurons of Drosophila (PMID 23979605). A missense variant in this same gene (p.Ala559Val), which had been previously identified in individuals with ADHD (PMID 16171832) and bipolar disorder (PMID 10889530), was observed in two unrelated male ASD probands (PMID 25313507). The p.Ala559Val variant has been experimentally shown to alter dopamine function and trafficking (PMIDs 18614672, 25313507). Campbell et al., 2019 characterized an in-frame deletion variant in the SLC6A3 gene (p.Asn336del) identified in an ASD proband from the Simons Simplex Collection, which had been inherited from a father with a broad autism phenotype, and demonstrated that this variant resulted in impaired dopamine transporter function in transfected cells and isolated Drosophila brain, as well as hyper-locomotion, increased grooming behavior, increased freezing following an audible fear stimulus, and impaired social interactions in flies.

Reports Added
[Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors.2019]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

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 in PMID 22495311) showed that this variant (T356M) resulted in anomalous dopamine transporter function and hyperactivity when expressed in the DA neurons of Drosophila (PMID 23979605). A missense variant in this same gene (p.Ala559Val), which had been previously identified in individuals with ADHD (PMID 16171832) and bipolar disorder (PMID 10889530), was observed in two unrelated male ASD probands (PMID 25313507). The p.Ala559Val variant has been experimentally shown to alter dopamine function and trafficking (PMIDs 18614672, 25313507). Campbell et al., 2019 characterized an in-frame deletion variant in the SLC6A3 gene (p.Asn336del) identified in an ASD proband from the Simons Simplex Collection, which had been inherited from a father with a broad autism phenotype, and demonstrated that this variant resulted in impaired dopamine transporter function in transfected cells and isolated Drosophila brain, as well as hyper-locomotion, increased grooming behavior, increased freezing following an audible fear stimulus, and impaired social interactions in flies.

Reports Added
[Structural, functional, and behavioral insights of dopamine dysfunction revealed by a deletion in SLC6A3.2019]
10/1/2014
icon
3

Increased from to 3

Description

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 in PMID 22495311) showed that this variant (T356M) resulted in anomalous dopamine transporter function and hyperactivity when expressed in the DA neurons of Drosophila (PMID 23979605). A missense variant in this same gene (p.Ala559Val), which had been previously identified in individuals with ADHD (PMID 16171832) and bipolar disorder (PMID 10889530), was observed in two unrelated male ASD probands (PMID 25313507). The p.Ala559Val variant has been experimentally shown to alter dopamine function and trafficking (PMIDs 18614672, 25313507).

Reports Added
[Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1).2000] [Sequence variation in the human dopamine transporter gene in children with attention deficit hyperactivity disorder.2005] [Anomalous dopamine release associated with a human dopamine transporter coding variant.2008] [Attention deficit/hyperactivity disorder-derived coding variation in the dopamine transporter disrupts microdomain targeting and trafficking regula...2012] [SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking.2014] [The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.2014]
Krishnan Probability Score

Score 0.49166248097235

Ranking 5276/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99703690247797

Ranking 1361/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.76371826907871

Ranking 1700/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 15.5

Ranking 127/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.50967764766656

Ranking 19341/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
TGFB1I1 Transforming growth factor beta-1-induced transcript 1 protein Human Protein Binding 7041 O43294
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