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Relevance to Autism

Deletion mutations in the EXT1 gene were detected in two boys from separate families presenting with hereditary multiple exostoses and autism associated with mental retardation (Li et al., 2002). Inactivation of the EXT1 gene in mice resulted in impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features (Irie et al., 2012).

Molecular Function

This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Appears to be a tumor suppressor. Mutations in this gene are responsible for multiple hereditary exostoses (an autosomal dominant disorder characterized by multiple projections of bone capped by cartilage), trichorhinophalangeal syndrome type II, and possibly chondrosarcoma.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Association of autism in two patients with hereditary multiple exostoses caused by novel deletion mutations of EXT1.
ASD
MR
Positive Association
Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ...
ASD
Support
Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.
ASD
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Highly Cited
The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate.
Recent Recommendation
Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate.
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN361R001 
 frameshift_variant 
 c.1742del 
 p.Val581GlyfsTer40 
 Familial 
 Paternal 
 Simplex 
 GEN361R002 
 frameshift_variant 
 c.2094del 
 p.Phe698LeufsTer8 
 Familial 
 Paternal 
 Simplex 
 GEN361R003 
 missense_variant 
 c.500C>T 
 p.Ser167Leu 
 De novo 
  
  
 GEN361R004 
 missense_variant 
 c.1600G>A 
 p.Val534Met 
 De novo 
  
 Simplex 
 GEN361R005 
 missense_variant 
 c.1772G>T 
 p.Gly591Val 
 De novo 
  
 Simplex 
 GEN361R006 
 frameshift_variant 
 c.1641_1642insCA 
 p.Ser548GlnfsTer74 
 De novo 
  
  
 GEN361R007 
 synonymous_variant 
 c.1503C>T 
 p.Leu501%3D 
 De novo 
  
 Simplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
8
Duplication
 1
 
8
Duplication
 1
 
8
Deletion
 2
 
8
Deletion
 3
 
8
Deletion
 1
 
8
Duplication
 4
 
8
Deletion
 4
 
8
Deletion
 2
 

Model Summary

Heparan Sulfate is critical for normal functioning of glutamatergic synapses and its deficiency mediates socio-communicative deficits and stereotypies characteristic for autism.

References

Type
Title
Author, Year
Primary
Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate.
Model Type: Genetic
Model Genotype: Homozygous
Mutation: Conditional deletion of 5 untranslated region of exon 1 to intron downstream of exon 1 of Ext gene using CamkII-cre, in excitatory neurons of the forebrain
Allele Type: Conditional loss-of-function
Strain of Origin: Not specified
Genetic Background: C57BL/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Not specified
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuronal activation following behavioral stimulation1
Decreased
 Immunohistochemistry
 3-4 weeks
Synaptic transmission1
Decreased
 Whole-cell patch clamp
 Unreported
Synaptic transmission1
Decreased
 Whole-cell patch clamp
 Unreported
Synaptic transmission1
Decreased
 Whole-cell patch clamp
 Unreported
Head bobbing1
Increased
 Hole-board test
 2-5 months
Pain or nociception1
Increased
 Hot plate test
 2-5 months
Social approach1
Decreased
 Resident-intruder test
 2-5 months
Nest building behavior1
Decreased
 Nest building assay
 2-5 months
Social interaction1
Decreased
 Separation-reunion test
 2-5 months
Social dominance1
Decreased
 Tube test of social dominance
 2-5 months
Ultrasonic vocalization1
Decreased
 Monitoring ultrasonic vocalizations
 2-5 months
Anxiety1
Decreased
 Light-dark exploration test
 2-5 months
Anxiety1
Decreased
 Elevated plus maze test
 2-5 months
Anxiety1
Decreased
 Open field test
 2-5 months
Protein expression level evidence1
Decreased
 Western blot
 Unreported
Size/growth1
 No change
 General observations
 2-5 months
Object recognition memory1
 No change
 Novel object recognition test
 2-5 months
Protein expression level evidence1
 No change
 Western blot
 Unreported
Grip strength1
 No change
 Inverted grid test
 2-5 months
Motor coordination and balance1
 No change
 Accelerating rotarod test
 2-5 months
Postural reflex1
 No change
 Righting reflex test
 2-5 months
Brain morphology1
 No change
 Histology
 4 months
Brain morphology1
 No change
 Golgi-cox staining
 Unreported
Neuronal activation following behavioral stimulation1
 No change
 Immunohistochemistry
 3-4 weeks
Presynaptic function: paired-pulse facilitation1
 No change
 Whole-cell patch clamp
 Unreported
Stereotypy1
 No change
 Observation of repetitive behavior
 2-5 months
Olfaction1
 No change
 Buried food test
 2-5 months
Sensorimotor gating1
 No change
 Prepulse inhibition
 2-5 months
Vision1
 No change
 Forepaw reaching test
 2-5 months
Social memory1
 No change
 Social recognition test
 2-5 months
 Not Reported: Circadian sleep/wake cycle, Immune response, Maternal behavior, Physiological parameters, Seizure


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
B3GNT1 UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 1 11041 O43505 IP; LC-MS/MS
Huttlin EL , et al. 2015
C19ORF46 Nesprin-4 163183 Q8N205-2 IP; LC-MS/MS
Huttlin EL , et al. 2015
CD79B B-cell antigen receptor complex-associated protein beta chain 974 P40259-2 IP; LC-MS/MS
Huttlin EL , et al. 2015
CHD8 chromodomain helicase DNA binding protein 8 57680 Q9HCK8 ChIP-chip
Subtil-Rodrguez A , et al. 2013
CNTF ciliary neurotrophic factor 1270 P26441 IP; MS
Ewing RM , et al. 2007
CRP C-reactive protein 1401 P02741 IP; LC-MS/MS
Huttlin EL , et al. 2015
ERGIC3 ERGIC and golgi 3 51614 A2TJK5 IP; LC-MS/MS
Huttlin EL , et al. 2015
EXT1 exostosin 1 2131 Q16394 IP/WB
McCormick C , et al. 2000
EXT2 exostosin glycosyltransferase 2 2132 J3KPT2 IP; LC-MS/MS
Huttlin EL , et al. 2015
Ext2 exostoses (multiple) 2 14043 P70428 IP/WB
McCormick C , et al. 2000
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
GAA Lysosomal alpha-glucosidase 2548 P10253 IP; LC-MS/MS
Huttlin EL , et al. 2015
LRRC33 Negative regulator of reactive oxygen species 375387 Q86YC3 IP; LC-MS/MS
Huttlin EL , et al. 2015
MPPE1 metallophosphoesterase 1 65258 Q53F39 IP; LC-MS/MS
Huttlin EL , et al. 2015
NAAA N-acylethanolamine acid amidase 27163 Q02083 IP; LC-MS/MS
Huttlin EL , et al. 2015
OSTF1 osteoclast stimulating factor 1 26578 Q92882 IP; MS
Ewing RM , et al. 2007
PEX19 peroxisomal biogenesis factor 19 5824 P40855 IP; LC-MS/MS
Huttlin EL , et al. 2015
PLAUR plasminogen activator, urokinase receptor 5329 Q03405 IP; LC-MS/MS
Huttlin EL , et al. 2015
PTCH1 patched 1 5727 Q13635 IP; LC-MS/MS
Huttlin EL , et al. 2015
SCGB2A2 Mammaglobin-A 4250 Q13296-2 IP; LC-MS/MS
Huttlin EL , et al. 2015
SLC39A5 Zinc transporter ZIP5 283375 Q6ZMH5 IP; LC-MS/MS
Huttlin EL , et al. 2015
Sotv CG8433 gene product from transcript CG8433-RA 3772101 Q9Y169 IP/WB
Han C , et al. 2004
SYP synaptophysin NM_003179 P08247 IP; LC-MS/MS
Huttlin EL , et al. 2015
TFR2 Transferrin receptor protein 2 E7ET36 IP; LC-MS/MS
Huttlin EL , et al. 2015
TOP3B topoisomerase (DNA) III beta 8940 O95985 HITS-CLIP
Xu D , et al. 2013
TOR1AIP2 torsin A interacting protein 2 163590 Q8NFQ8 IP; LC-MS/MS
Huttlin EL , et al. 2015
TRAP1 TNF receptor-associated protein 1 10131 Q12931 Y2H
Simmons AD , et al. 1999

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