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Relevance to Autism

Several studies have found rare single gene variations in the CNTN4 gene in patients with ASD. These variations include deletions, missense mutations and a duplication. For example, a deletion in the CNTN4 gene was found in a patient with PDD-NOS and mild intellectual disability (Leblond et al., 2012). On the contrary, one study attempted to find a genetic association between CNTN4 variants and autism in a sample of CORA families but did not find any statistically significant results.

Molecular Function

This gene encodes a member of the contactin family of immunoglobulins. Contactins are axon-associated cell adhesion molecules that function in neuronal network formation and plasticity. The encoded protein is a glycosylphosphatidylinositol-anchored neuronal membrane protein that may play a role in the formation of axon connections in the developing nervous system.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Disruption of contactin 4 in three subjects with autism spectrum disorder.
ASD
Positive Association
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
SCZ
Positive Association
Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations.
ASD
Positive Association
A candidate gene association study further corroborates involvement of contactin genes in autism.
ASD
Positive Association
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.
ASD
Negative Association
No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti...
ASD
Support
Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder.
ASD
Support
Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications.
ASD
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders.
ASD
ID
Support
A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
ASD
Support
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.
ASD
ID
Support
Contactin 4 as an autism susceptibility locus.
ASD
Support
Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with develop...
ID
Behavioral abnormalities
Highly Cited
Overlapping and differential expression of BIG-2, BIG-1, TAG-1, and F3: four members of an axon-associated cell adhesion molecule subgroup of the i...
Highly Cited
Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome.
ASD
DD, ID
Recent Recommendation
Human-specific histone methylation signatures at transcription start sites in prefrontal neurons.
Recent Recommendation
The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules.
Recent Recommendation
Disruption of Contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome.
Recent Recommendation
BIG-2 mediates olfactory axon convergence to target glomeruli.
Recent Recommendation
Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN050R001 
 copy_number_loss 
  
  
 Familial 
 Paternal 
 Multiplex 
 GEN050R002 
 copy_number_gain 
  
  
 Familial 
 Paternal 
 Simplex 
 GEN050R003 
 copy_number_loss 
  
  
  
  
 Multiplex 
 GEN050R004 
 copy_number_gain 
  
  
  
  
 Multiplex 
 GEN050R005 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN050R006 
 missense_variant 
 c.532A>G 
 p.Asn178Asp 
 Familial 
 Maternal 
  
 GEN050R007 
 missense_variant 
 c.662G>A 
 p.Gly221Asp 
 Familial 
 Maternal 
  
 GEN050R008 
 missense_variant 
 c.992A>G 
 p.Glu331Gly 
 Familial 
 Paternal 
  
 GEN050R009 
 missense_variant 
 c.1889A>G 
 p.Tyr630Cys 
 Familial 
 Paternal 
  
 GEN050R010 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN050R011 
 copy_number_loss 
  
  
 Familial 
  
 Multiplex 
 GEN050R012 
 copy_number_gain 
  
  
 Unknown 
  
 Unknown 
 GEN050R013 
 copy_number_loss 
  
  
 Unknown 
  
 Simplex 
 GEN050R014 
 translocation 
  
  
 De novo 
 NA 
  
 GEN050R015 
 missense_variant 
 c.1814T>C 
 p.Ile605Thr 
 De novo 
 NA 
  
 GEN050R016 
 splice_site_variant 
 c.1942+2T>C 
  
 Familial 
 Paternal 
  
 GEN050R017 
 complex_structural_alteration 
  
  
 De novo 
 NA 
  

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN050C001 
 intron_variant 
 rs7641285 
 c.-145+105534C>T;c.-145+38822C>T 
 Allele 1, G; allele 2, A 
 67 ASD patients and 117 healthy controls 
 Discovery 
 GEN050C002 
 intron_variant 
 rs908487 
 c.56-9357T>C 
 A/G 
 67 ASD patients and 117 healthy controls 
 Discovery 
 GEN050C003 
 intron_variant 
 rs17008493 
 c.-145+55783T>A;c.-145+57444T>A;c.-145+56773T>A;c.-145+56792T>A 
  
 166 Japanese ASD probands, 642 healthy Japanese controls 
 Discovery 
 GEN050C004 
 intron_variant 
 rs35346733 
 c.-88-91778G>A 
  
 40,675 SCZ cases and 64,643 controls (CLOZUK and independent PGC datasets) 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
3
Deletion-Duplication
 17
 
3
N/A
 2
 
3
Deletion-Duplication
 53
 
3
Duplication
 1
 
3
Duplication
 1
 
3
Duplication
 1
 
3
Duplication
 2
 
3
Deletion
 2
 
3
Deletion
 4
 
3
Duplication
 11
 
3
Duplication
 1
 

Model Summary

Cntn4 is one of the axon guidance molecules crucial for the formation and maintenance of functional odor map in the olfactory bulb.

References

Type
Title
Author, Year
Primary
BIG-2 mediates olfactory axon convergence to target glomeruli.
Additional
Heterogeneity of Cell Surface Glutamate and GABA Receptor Expression in Shank and CNTN4 Autism Mouse Models.

M_CNTN4_1_KI_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: A floxed neo cassette and transcription/translation stop signal (stop) inserted at a start codon (ATG) in the exon 2 of cntn4 gene.
Allele Type: Targeted (knock-out)
Strain of Origin: 129S/SvEv
Genetic Background: 129S/SvEv * C57BL/6
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_CNTN4_1_KI_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuroreceptor levels: glutamate receptors: ampa receptors2
Increased
Description: Mutants show increased cell surface glutamate receptor levels in the striatum. Mutants show increased cell surface expression levels of GluA2 and GluA1 in the striatum.
 Western blot
 3-6 months
Neuroreceptor levels: gaba-r: gabaa2
Decreased
Description: Mutants show reduced cell surface GABAARa1 levels in the hippocampus andthalamus and a trend for reduced cell surface GABAARa1 levelsin the cortex.
 Western blot
 3-6 months
Neuroreceptor levels: glutamate receptors: nmda receptors2
Decreased
Description: Mutants show reduced cell surface glutamate receptor levels in the cortex and hippocampus compared to controls. Mutants show reduced cell surface expression levels of GluN1 in the cortex.
 Western blot
 3-6 months
Anatomical projections and connectivity1
Decreased
Description: Ectopic glomerular targeting of Olfactory Sensory Neuron axons
Exp Paradigm: Immunohistochemistry
 Immunohistochemistry
 6- 8 weeks
Neuroreceptor levels: glutamate receptors: ampa receptors2
Decreased
Description: Mutants show reduced cell surface glutamate receptor levels in the cortex and hippocampus compared to controls. Mutants show reduced cell surface expression levels of GluA2 in the cortex. Mutants show reduced cell surface expression levels of GluA2 and mG
 Western blot
 3-6 months
General characteristics1
 No change
 General observations
 Unreported
Neuroreceptor levels: gaba-r: gabaa2
 No change
 Western blot
 3-6 months
Neuroreceptor levels: glutamate receptors: ampa receptors2
 No change
 Western blot
 3-6 months
Neuroreceptor levels: glutamate receptors: nmda receptors2
 No change
 Western blot
 3-6 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, 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
AMY1A amylase, alpha 1A (salivary) 276 Q6NSB3 Y2H; IP; MS; IP/WB
Ishizaki R , et al. 2006
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
PRKAR2B protein kinase, cAMP-dependent, regulatory, type II, beta 5577 P31323 IP/WB
Islam A , et al. 2008
Auts2 autism susceptibility candidate 2 319974 Q6PED7 ChIP-Seq
Oksenberg N , et al. 2014
Ptprg protein tyrosine phosphatase, receptor type, G 19270 Q05909 Affinity chromatography
Bouyain S and Watkins DJ 2010
Zbtb20 zinc finger and BTB domain containing 20 56490 Q8K0L9 ChIP-Seq; Gene microarray
Rasmussen MB , et al. 2014

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