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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
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
DD, epilepsy/seizures
ASD, ID
Support
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes
ASD
Support
Monogenic developmental and epileptic encephalopathies of infancy and childhood
ADD, ID, epilepsy/seizures
Support
Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.
ASD
ID
Support
Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency
Cerebral creatine deficiency syndrome 1
Support
Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.
ASD
Epilepsy/seizures, Cerebral creatine deficiency sy
Support
Case report: Clinical and magnetic resonance spectroscopy presentation of a female severely affected with X-linked creatine transporter deficiency
Cerebral creatine deficiency syndrome 1, ASD, DD,
Support
Diagnostic exome sequencing in persons with severe intellectual disability.
ID
Epilepsy, ASD
Support
ASD, DD
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
Autism spectrum disorder and comorbid neurodevelopmental disorders (ASD-NDDs): Clinical and genetic profile of a pediatric cohort
ASD
Epilepsy/seizures
Support
Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1.
ID
Support
DD, epilepsy/seizures
Support
Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.
ASD
Support
SLC gene mutations and pediatric neurological disorders: diverse clinical phenotypes in a Saudi Arabian population
ASD, ADHD, DD, ID, epilepsy/seizures
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
Support
ASD
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
Integrating de novo and inherited variants in 42
ASD
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
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.
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 
  
  
 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 
  
 Simplex 
 GEN236R008 
 inframe_deletion 
 1215+TTC(delTTC) 
 -405 
 De novo 
  
 Simplex 
 GEN236R009 
 synonymous_variant 
 c.1494C>T 
 p.Tyr498= 
 De novo 
  
 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 
  
  
 GEN236R016 
 inframe_deletion 
 c.1361_1362+1del 
  
 Familial 
 Maternal 
 Multi-generational 
 GEN236R017 
 missense_variant 
 c.1145C>T 
 p.Pro382Leu 
 Familial 
 Maternal 
 Unknown 
 GEN236R018 
 stop_gained 
 c.1540C>T 
 p.Arg514Ter 
 Familial 
 Maternal 
  
 GEN236R019 
 inframe_deletion 
 c.740_745del 
 p.Tyr247_Phe248del 
 Familial 
 Maternal 
  
 GEN236R020 
 stop_gained 
 c.1540C>T 
 p.Arg514Ter 
 De novo 
  
 Simplex 
 GEN236R021 
 missense_variant 
 c.1196C>A 
 p.Ala399Asp 
 De novo 
  
  
 GEN236R022 
 inframe_deletion 
 c.442_444del 
 p.Tyr148del 
 De novo 
  
  
 GEN236R023 
 inframe_deletion 
 c.942_944del 
 p.Phe315del 
 De novo 
  
 Simplex 
 GEN236R024 
 splice_region_variant 
 c.263-6C>T 
  
 Familial 
 Paternal 
  
 GEN236R025 
 missense_variant 
 c.1405G>C 
 p.Val469Leu 
 Familial 
 Maternal 
  
 GEN236R026 
 missense_variant 
 c.644A>G 
 p.Glu215Gly 
 Familial 
 Maternal 
 Simplex 
 GEN236R027 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN236R028 
 missense_variant 
 c.497C>T 
 p.Thr166Met 
 Unknown 
  
 Multiplex 
 GEN236R029 
 inframe_deletion 
 c.940_942delTTC 
 p.Phe315del 
 Unknown 
  
  
 GEN236R030 
 missense_variant 
 c.1661C>T 
 p.Pro554Leu 
 Unknown 
  
  
 GEN236R031 
 frameshift_variant 
 c.974_975del 
 p.Thr325SerfsTer139 
 Unknown 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion
 1
 
X
Duplication
 1
 
X
Deletion-Duplication
 22
 
X
Deletion
 2
 
X
Deletion
 1
 
X
Deletion
 2
 
X
Deletion-Duplication
 1
 
X
Deletion
 2
 
X
Deletion-Duplication
 1
 
X
Deletion
 12
 
X
Deletion-Duplication
 82
 

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.
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
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Synapse density: inhibitory1
Decreased
 Immunohistochemistry
 6 months
Hippocampal morphology1
Decreased
 Immunohistochemistry
 6 months
Cell proliferation: neural precursors1
Decreased
 Immunohistochemistry
 6 months
Perseveration1
Increased
 Accelerating rotarod test
 1.4, 3.4, 6 months
Self grooming: perseveration1
Increased
 Grooming behavior assessments
 6 months
Bioactive compound levels: guanidinoacetic acid (gaa)1
Increased
 Gas chromatography-mass spectrometry (gc-ms)
 1, 6 months
Bioactive compound levels: guanidinoacetic acid (gaa)1
Decreased
 Gas chromatography-mass spectrometry (gc-ms)
 1 month
Bioactive compound levels: creatine1
Decreased
 Gas chromatography-mass spectrometry (gc-ms)
 1, 6 months
Size/growth1
Decreased
 Body weight measurement
 2, 3.4, 6 months
Microgliosis1
Increased
 Immunohistochemistry
 6 months
Object recognition memory: long-term recall1
Decreased
 Novel object recognition test
 4 weeks, 2, 3.4, 6 months
Spatial working memory1
Decreased
 Y-maze test
 4 weeks, 3.4, 6 months
Object recognition memory1
Decreased
 Novel object recognition test
 6 months
Spatial reference memory1
Decreased
 Morris water maze test
 1.4, 3.4, 6 months
Spatial learning1
Decreased
 Morris water maze test
 1.4, 3.4, 6 months
Cell senescence1
Increased
 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





Download SLC6A8's Cytoscape file

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
Cd59 CD59 molecule, complement regulatory protein 25407 P27274 IP/WB
Wang W , et al. 2002
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
Prkaa1 protein kinase, AMP-activated, alpha 1 catalytic subunit 65248 P54645 GST
Li H , et al. 2010
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

AGTR1
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