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Relevance to Autism

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. As well, rare variants in the SLC6A8 gene have been identified with autism (Po-Argelles et al., 2006).

Molecular Function

The encoded protein has creatine:sodium symporter activity.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
X-Linked creatine transporter deficiency in two patients with severe mental retardation and autism.
ASD
MR, epilepsy, dystonia
Support
Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.
ASD
Support
Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.
ID
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
ASD
Support
Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.
ASD
ID
Support
Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.
ASD
Epilepsy/seizures, Cerebral creatine deficiency sy
Support
Diagnostic exome sequencing in persons with severe intellectual disability.
ID
Epilepsy, ASD
Support
A novel SLC6A8 mutation associated with intellectual disabilities in a Chinese family exhibiting creatine transporter deficiency: case report.
Cerebral creatine deficiency syndrome 1
DD, ID, epilepsy/seizures, autistic features
Support
Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1.
ID
Support
Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.
ASD
Support
Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.
Cerebral creatine deficiency syndrome 1
ID
Support
Whole genome sequencing of 45 Japanese patients with intellectual disability
DD, ID
Highly Cited
X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome.
Recent Recommendation
Overexpression of wild-type creatine transporter (SLC6A8) restores creatine uptake in primary SLC6A8-deficient fibroblasts.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN236R001 
 frameshift_variant 
 c.878_879del 
 p.Leu293GlnfsTer3 
 Familial 
 Maternal 
 Simplex 
 GEN236R002 
 inframe_deletion 
 c.1192_1194del 
 p.Phe398del 
 Familial 
 Maternal 
 Simplex 
 GEN236R003 
 missense_variant 
 c.1649C>G 
 p.Thr550Ser 
 Unknown 
  
 Multiplex 
 GEN236R004 
 inframe_deletion 
 c.1006_1008del 
 p.Asn336del 
 De novo 
 NA 
  
 GEN236R005 
 missense_variant 
 c.1169C>T 
 p.Pro390Leu 
  
  
  
 GEN236R006 
 missense_variant 
 c.1430C>T 
 p.Ser477Leu 
  
  
  
 GEN236R007 
 splice_site_variant 
 c.913-1G>T 
  
 De novo 
 NA 
 Simplex 
 GEN236R008 
 inframe_deletion 
 1215+TTC(delTTC) 
 -405 
 De novo 
 NA 
 Simplex 
 GEN236R009 
 synonymous_variant 
 c.1494C>T 
 p.Tyr498= 
 De novo 
 NA 
 Simplex 
 GEN236R010 
 frameshift_variant 
 c.205_206del 
 p.Ala69ArgfsTer119 
 Unknown 
  
 Unknown 
 GEN236R011 
 missense_variant 
 c.644A>G 
 p.Glu215Gly 
 Familial 
 Maternal 
 Simplex 
 GEN236R012 
 missense_variant 
 c.1139C>A 
 p.Ser380Ter 
 Familial 
  
 Simplex 
 GEN236R013 
 missense_variant 
 c.1181C>A 
 p.Thr394Lys 
 Familial 
 Maternal 
 Multiplex 
 GEN236R014 
 stop_gained 
 c.1540C>T 
 p.Arg514Ter 
 Familial 
 Maternal 
  
 GEN236R015 
 missense_variant 
 c.947C>T 
 p.Ser316Phe 
 De novo 
 NA 
  
 GEN236R016 
 inframe_deletion 
 c.1361_1362+1del 
  
 Familial 
 Maternal 
 Multi-generational 
 GEN236R017 
 missense_variant 
 c.1145C>T 
 p.Pro382Leu 
 Familial 
 Maternal 
 Unknown 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion
 1
 
X
Duplication
 1
 
X
Deletion-Duplication
 18
 
X
Deletion
 2
 
X
Deletion
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 1
 
X
Deletion
 2
 
X
Deletion-Duplication
 1
 
X
Deletion
 7
 
X
Deletion-Duplication
 65
 

Model Summary

Longitudinal analysis of behavior in creatinine deficiency syndrome modeled in the SLC6A8 hemizygous knockout mice show progressive impairment of short and long-term declarative memory indicating abnormally early aging of the brain. Pathological examinations of SLC6A8 hemizygous knockout mice show loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and accumulation of autofluorescent lipofucsin.

References

Type
Title
Author, Year
Primary
A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging.

M_SLC6A8_1_HE

Model Type: Genetic
Model Genotype: Hemizygous
Mutation: Male mice with one allele of Slc6A8 knocked out were generated by FLP/CRE recombination by introducing loxP sites flanking exon 57 of the gene in embryonic stem cells. As CrT deficiency is an X-linked pathology male mice were selected for this study.
Allele Type: Targeted(knockout)
Strain of Origin: C57BL/6 J
Genetic Background: C57BL/6 J
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Unreported

M_SLC6A8_2_CKO_HE

Model Type: Genetic
Model Genotype: Hemizygous
Mutation: Conditional deletion of exon 27 of Slc6a8 gene using Nestin-cre, in neuronal, glial and other cell types including blood brain barrier endothelial cells, in the central and peripheral nervous system. As creatine transporter deficiency is an X-linked pathology, male mice were selected for this study.
Allele Type: Conditional loss-of-function
Strain of Origin: C57BL/6 J
Genetic Background: C57BL/6 J
ES Cell Line: 129/Sv* C57BL/6N
Mutant ES Cell Line: Unreported
Model Source: Unreported

M_SLC6A8_1_HE

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Hippocampal morphology1
Decreased
Description: Slc6a8 hemizygous mice show decreased hippocampal volume compared to controls
Exp Paradigm: Male only
 Immunohistochemistry
 6 months
Cell proliferation: neural precursors1
Decreased
Description: Slc6a8 hemizygous mice show decreased number of neuronal precursors in the hippocampal dentate gyrus compared to controls
Exp Paradigm: Male only
 Immunohistochemistry
 6 months
Synapse density: inhibitory1
Decreased
Description: Slc6a8 hemizygous mice show decreased inhibitory synapses in all layers of the pfc and acc, compared to controls
Exp Paradigm: Prefrontal cortex and anterior cingulate cortex examined, male only
 Immunohistochemistry
 6 months
Self grooming: perseveration1
Increased
Description: Slc6a8 hemizygous mice show increased self-grooming compared to controls
Exp Paradigm: Male only
 Grooming behavior assessments
 6 months
Perseveration1
Increased
Description: Slc6a8 hemizygous mice show increased in the latency of fall compared to control mice
Exp Paradigm: Male only
 Accelerating rotarod test
 1.4, 3.4, 6 months
Size/growth1
Decreased
Description: Slc6a8 hemizygous mice had reduced body weight compared to controls
Exp Paradigm: Male only
 Body weight measurement
 2, 3.4, 6 months
Microgliosis1
Increased
Description: Slc6a8 hemizygous mice show increased number of activated microglia and a corresponding decrease in resting microglia compared to controls
Exp Paradigm: Prefrontal cortex and anterior cingulate cortex examined, male only
 Immunohistochemistry
 6 months
Spatial working memory1
Decreased
Description: Slc6a8 hemizygous mice show a decrease in the number of spontaneous alternations of entries into the arms compared to controls
Exp Paradigm: Male only, y-maze test spontaneous alternation
 Y-maze test
 4 weeks, 3.4, 6 months
Object recognition memory1
Decreased
Description: Slc6a8 hemizygous mice show decrease in short-term objection recognition compared to controls at 6 months
Exp Paradigm: Male only
 Novel object recognition test
 6 months
Spatial reference memory1
Decreased
Description: During probe trial in the mwm, slc6a8 hemizygous mice explored the four quadrants of the maze for the missing platform while control animals spent significantly longer time in the quadrant where the platform was located during the training days
Exp Paradigm: During probe trial the escape platform was removed from the tank and the swimming paths were recorded over 60 s while mice searched for the missing platform
 Morris water maze test
 1.4, 3.4, 6 months
Spatial learning1
Decreased
Description: Slc6a8 hemizygous mice could not remember the location of the platform and explored all quadrants equally whereas control mice spent more time in the quadrant where the platform was located during training
Exp Paradigm: Males only
 Morris water maze test
 1.4, 3.4, 6 months
Object recognition memory: long-term recall1
Decreased
Description: Slc6a8 hemizygous mice show decreased long-term object recognition at 24 hours, compared to controls
Exp Paradigm: Male only
 Novel object recognition test
 4 weeks, 2, 3.4, 6 months
Cell senescence1
Increased
Description: Slc6a8 hemizygous mice show increased cellular aging than controls
Exp Paradigm: Male only
 Lipofuscin accumulation
 6 months
Anxiety1
 No change
 Open field test
 1.4, 3.4, 6 months
Exploratory activity1
 No change
 Y-maze test
 4 weeks, 3.4, 6 months
Object recognition memory1
 No change
 Novel object recognition test
 4 weeks, 3.4 months
General locomotor activity1
 No change
 Home cage behavior
 Adult
Cortical thickness1
 No change
 Immunohistochemistry
 6 months
Neuronal number1
 No change
 Immunohistochemistry
 6 months
Synapse density: excitatory1
 No change
 Immunohistochemistry
 6 months
Bioactive compound levels: creatine1
 No change
 Gas chromatography-mass spectrometry (gc-ms)
 6 months
Bioactive compound levels: guanidinoacetic acid (gaa)1
 No change
 Gas chromatography-mass spectrometry (gc-ms)
 1, 6 months
Self grooming: perseveration1
 No change
 Grooming behavior assessments
 1.4 months
Social approach1
 No change
 Three-chamber social approach test
 6 months
Social memory1
 No change
 Three-chamber social approach test
 6 months
 Not Reported: Circadian sleep/wake cycle, Communications, Maternal behavior, Neurophysiology, Physiological parameters, Seizure, Sensory

M_SLC6A8_2_CKO_HE

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Cell proliferation: neural precursors1
Decreased
Description: Slc6a8 cko hemizygous mice show decreased number of total dividing cells in the dentate gyrus compared to controls
Exp Paradigm: Male only
 Immunohistochemistry
 6 months
Spatial working memory1
Decreased
Description: Slc6a8 cko hemizygous mice show a decrease in the number of spontaneous alternations of entries into the arms compared to controls
Exp Paradigm: Male only, y maze spontaneous alternation
 Y-maze test
 4 weeks, 3.4, 6 months,
Object recognition memory: long-term recall1
Decreased
Description: Slc6a8 cko hemizygous mice show decreased long-term object recognition at 24 hours, compared to controls, at 4 weeks, 2, 3.4 and 6 months
Exp Paradigm: Male only
 Novel object recognition test
 4 weeks, 2, 3.4, 6 months
Object recognition memory1
Decreased
Description: Slc6a8 cko hemizygous mice show decreased object recognition compared to controls at 4 weeks and 3.4 months
Exp Paradigm: Male only
 Novel object recognition test
 4 weeks, 3.4 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Maternal behavior, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
AGTR1 angiotensin II receptor, type 1 185 P30556 IP; LC-MS/MS
Huttlin EL , et al. 2015
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
GRPR gastrin-releasing peptide receptor 2925 P30550 IP; LC-MS/MS
Huttlin EL , et al. 2015
NT5E 5'-nucleotidase 4907 P21589 IP; LC-MS/MS
Huttlin EL , et al. 2015
PTGIR Prostacyclin receptor 5739 P43119 IP; LC-MS/MS
Huttlin EL , et al. 2015
TPRA1 Transmembrane protein adipocyte-associated 1 131601 Q86W33-2 IP; LC-MS/MS
Huttlin EL , et al. 2015
YIPF3 Yip1 domain family, member 3 25844 Q9GZM5 IP; LC-MS/MS
Huttlin EL , et al. 2015
Cd59 CD59 molecule, complement regulatory protein 25407 P27274 IP/WB
Wang W , et al. 2002
Prkaa1 protein kinase, AMP-activated, alpha 1 catalytic subunit 65248 P54645 GST
Li H , et al. 2010

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