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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

        

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.
ASD
Positive Association
Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism.
ADHD
Positive Association
Variation of the genes encoding the human glutamate EAAT2, serotonin and dopamine transporters and Susceptibility to idiopathic generalized epilepsy.
Epilepsy
Support
Attention deficit/hyperactivity disorder-derived coding variation in the dopamine transporter disrupts microdomain targeting and trafficking regula...
ADHD
Support
Anomalous dopamine release associated with a human dopamine transporter coding variant.
Support
Sequence variation in the human dopamine transporter gene in children with attention deficit hyperactivity disorder.
ADHD
Support
SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population
DD
Support
Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1).
BPD
Support
Structural, functional, and behavioral insights of dopamine dysfunction revealed by a deletion in SLC6A3.
ASD
Support
Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (hDAT R51W) in dopamine neurotransmis...
ASD
Support
Missense dopamine transporter mutations associate with adult parkinsonism and ADHD.
ADHD, early-onset parkinsonism
Highly Cited
Association of attention-deficit disorder and the dopamine transporter gene.
ADHD
Recent Recommendation
SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking.
ASD
Recent Recommendation
Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors.
ASD
Recent Recommendation
Neuropsychiatric disease-associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes.
Recent Recommendation
The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN568R001 
 missense_variant 
 c.1067C>T 
 p.Thr356Met 
 De novo 
  
 Simplex 
 GEN568R002 
 missense_variant 
 c.1676C>T 
 p.Ala559Val 
 Familial 
 Maternal 
 Simplex 
 GEN568R003 
 missense_variant 
 c.1676C>T 
 p.Ala559Val 
 Familial 
 Maternal 
 Multiplex 
 GEN568R004 
 missense_variant 
 c.*163A>G 
  
 Familial 
 Maternal 
 Simplex 
 GEN568R005 
 missense_variant 
 c.1676C>T 
 p.Ala559Val 
 Unknown 
 Not maternal 
 Multi-generational 
 GEN568R006 
 missense_variant 
 c.1805A>G 
 p.Glu602Gly 
 Familial 
 Paternal 
 Simplex 
 GEN568R007 
 missense_variant 
 c.151C>T 
 p.Arg51Trp 
 Familial 
 Maternal 
 Multiplex 
 GEN568R008 
 missense_variant 
 c.934A>T 
 p.Ile312Phe 
 Unknown 
 Not maternal 
 Simplex 
 GEN568R009 
 missense_variant 
 c.1261G>A 
 p.Asp421Asn 
 Unknown 
  
 Simplex 
 GEN568R010 
 inframe_deletion 
  
 p.Asn336del 
 Familial 
 Paternal 
 Simplex 
 GEN568R011a 
 inframe_deletion 
 c.1078_1080del 
 p.Ser360del 
 Familial 
 Both parents 
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
5
Deletion-Duplication
 36
 
5
Duplication
 1
 
5
Duplication
 2
 
5
Deletion
 1
 
5
Deletion
 2
 
5
Deletion
 3
 
5
Deletion
 4
 
5
Deletion
 10
 
5
Deletion
 4
 
5
Deletion
 4
 

Model Summary

The dopamine transporter, Slc6a3 is knocked out in the model and homozygotes for targeted null mutations exhibit hyperactivity and impaired spatial cognitive function.

References

Type
Title
Author, Year
Additional
Impaired spatial working memory and decreased frontal cortex BDNF protein level in dopamine transporter knockout mice.
Additional
Pregnenolone rescues schizophrenia-like behavior in dopamine transporter knockout mice.
Additional
Genetic targeting of the amphetamine and methylphenidate-sensitive dopamine transporter: on the path to an animal model of attention-deficit hypera...
Additional
The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.
Additional
Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors.
Additional
Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice.
Model Type: Genetic
Model Genotype: Homozygous
Mutation: The DAT or Slc6a3 gene was inactivated by replacement of exon I and exon II with a neomycin resistance cassette.
Allele Type: Targeted (Knock-out)
Strain of Origin: 129SvEv
Genetic Background: C57BL/6*129Sv/J
ES Cell Line:
Mutant ES Cell Line:
Model Source:
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Spatial working memory1
Decreased
 Y-maze test
 8-11 weeks
Regulation of gene expression1
Decreased
 Elisa
 8-11 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Maternal behavior, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
CAMK2A calcium/calmodulin-dependent protein kinase II alpha 815 Q9UQM7 Biotinylation assay; IP/WB
Sakrikar D , et al. 2012
Ctr9 CTR9 homolog, Paf1/RNA polymerase II complex component 293184 G3V897 Y2H; IP/WB; Co-localization
De Gois S , et al. 2015
DRD2 dopamine receptor D2 1813 P14416 IP/WB; GST; in vitro binding assay
Lee FJ , et al. 2007
EPN1 epsin 1 NM_013333 Q9Y6I3 Immunofluorescence; IP/WB; Biotinylation assay
Sorkina T , et al. 2006
EPS15 epidermal growth factor receptor pathway substrate 15 2060 B7Z240 Immunofluorescence; IP/WB; Biotinylation assay
Sorkina T , et al. 2006
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
NEDD4 neural precursor cell expressed, developmentally down-regulated 4 4734 P46934 Immunofluorescence; IP/WB; Biotinylation assay
Sorkina T , et al. 2006
PARK2 parkinson protein 2, E3 ubiquitin protein ligase (parkin) 5071 O60260 Biotinylation assay; IP/WB
IP/WB; WB
Jiang H , et al. 2004
PARK2 parkinson protein 2, E3 ubiquitin protein ligase (parkin) 5071 O60260 Biotinylation assay; IP/WB
IP/WB; WB
Jiang H , et al. 2004
PICK1 protein interacting with PRKCA 1 9463 Q9NRD5 Y2H; IP/WB
Torres GE , et al. 2001
PRKCB protein kinase C, beta 25023 P68403 IP/WB
Johnson LA , et al. 2005
SNCA synuclein, alpha (non A4 component of amyloid precursor) 6622 P37840 IP/WB
Wersinger C and Sidhu A 2005
STX1A syntaxin 1A (brain) 6804 Q16623 GST; IP/WB
Binda F , et al. 2008
TGFB1I1 Transforming growth factor beta-1-induced transcript 1 protein 7041 O43294 IP/WB; GST; Biotinylation assay
Carneiro AM , et al. 2002
TUBA1B Tubulin alpha-1B chain 500929 Q6P9V9 IP/WB
Wersinger C and Sidhu A 2005
TUBB1 Protein Tubb1 679312 M0R8B6 IP/WB
Wersinger C and Sidhu A 2005
UBC ubiquitin C 7316 P63279 Immunofluorescence; IP/WB; Biotinylation assay
Sorkina T , et al. 2006

TUBA1B
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