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Relevance to Autism

Cntnap4 mutant mice display augmented midbrain dopaminergic release in the nucleus accumbens, a severe and highly penetrant over-grooming behavior, elevated startle responses and abnormal PPI indexes. Furthermore, deletions involving the CNTNAP4 gene were identified in patients with ASD, ADHD, and schizophrenia (Karayannis et al., 2014).

Molecular Function

This gene product belongs to the neurexin family, members of which function in the vertebrate nervous system as cell adhesion molecules and receptors.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.
ASD
SCZ, ADHD
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
Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics.
ASD
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD
Support
Functional impact of global rare copy number variation in autism spectrum disorders.
ASD
Support
Analysis of recent shared ancestry in a familial cohort identifies coding and noncoding autism spectrum disorder variants
ASD
Support
Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.
Epilepsy
Support
Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.
ASD
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
The contribution of de novo coding mutations to autism spectrum disorder
ASD
Support
ASD
DD, ID
Support
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD
Recent Recommendation
Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN616R001 
 copy_number_loss 
  
  
 Unknown 
  
 Unknown 
 GEN616R002 
 copy_number_loss 
  
  
 Familial 
  
 Unknown 
 GEN616R003 
 copy_number_loss 
  
  
 Unknown 
  
 Unknown 
 GEN616R004 
 copy_number_loss 
  
  
 Unknown 
  
 Unknown 
 GEN616R005 
 copy_number_loss 
  
  
 Unknown 
  
 Unknown 
 GEN616R006 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Unknown 
 GEN616R007 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Unknown 
 GEN616R008 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN616R009 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN616R010 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN616R011 
 copy_number_gain 
  
  
 De novo 
  
  
 GEN616R012 
 copy_number_gain 
  
  
 Unknown 
  
 Possible multi-generational 
 GEN616R013 
 nonsynonymous_variant 
  
  
 Unknown 
  
 Unknown 
 GEN616R014 
 missense_variant 
 c.3094A>T 
 p.Asn1032Tyr 
 De novo 
  
 Simplex 
 GEN616R015 
 missense_variant 
 c.2077A>G 
 p.Ile693Val 
 De novo 
  
 Simplex 
 GEN616R016 
 missense_variant 
 c.3508G>A 
 p.Asp1170Asn 
 De novo 
  
  
 GEN616R017 
 missense_variant 
 c.1538A>G 
 p.His513Arg 
 Familial 
  
 Simplex 
 GEN616R018a 
 intron_variant 
 c.193+679_193+682del 
  
 Familial 
 Both parents 
 Simplex 
 GEN616R019 
 missense_variant 
 c.2008A>C 
 p.Asn670His 
 De novo 
  
  
 GEN616R020 
 missense_variant 
 c.2008A>C 
 p.Asn670His 
 De novo 
  
  
 GEN616R021 
 missense_variant 
 c.2008A>C 
 p.Asn670His 
 De novo 
  
  
 GEN616R022 
 missense_variant 
 c.2008A>C 
 p.Asn670His 
 De novo 
  
  
 GEN616R023a 
 missense_variant 
 c.3586G>A 
 p.Val1196Met 
 Unknown 
  
  
 GEN616R023b 
 missense_variant 
 c.2008A>C 
 p.Asn670His 
 De novo 
  
  
 GEN616R024 
 missense_variant 
 c.320G>C 
 p.Ser107Thr 
 De novo 
  
  
 GEN616R025 
 inframe_deletion 
 c.1342_1371del 
 p.Asn448_Leu457del 
 De novo 
  
  
 GEN616R026 
 missense_variant 
 c.2701G>A 
 p.Ala901Thr 
 De novo 
  
  
 GEN616R027 
 synonymous_variant 
 c.3810T>C 
 p.Tyr1270%3D 
 De novo 
  
  
 GEN616R028 
 missense_variant 
 c.2701G>A 
 p.Ala901Thr 
 De novo 
  
 Simplex 
 GEN616R029 
 frameshift_variant 
 c.3658_3661del 
 p.Asp1220IlefsTer5 
 Familial 
 Maternal 
 Simplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
16
Duplication
 2
 
16
Duplication
 1
 
16
Deletion
 2
 
16
Duplication
 2
 
16
Duplication
 1
 
16
Deletion
 1
 
16
Deletion-Duplication
 49
 

Model Summary

Cntnap4 null mice have increased levels of dopamine and decreased levels of Gabaergic signaling. They show abnormal perseverative allo-grooming behavior and impaired sensorimotor gating.

References

Type
Title
Author, Year
Primary
Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.
ASD, ADHD, Schizophrenia
Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.
Model Type: Genetic
Model Genotype: Heterozygous
Mutation: The targeting vector was designed to replace 585 bp of the first exon of the gene and contained an inframe eEGFP followed by a new gene. Correctly targeted ES cell lines were used to produce chimaeric mice that were in turn mated with ICR females. This line was backcrossed only once with ICR after germline transmission and then was intercrossed in the following generations.
Allele Type:
Strain of Origin: 129SvJ
Genetic Background: ICR*129S1
ES Cell Line: R1
Mutant ES Cell Line:
Model Source:
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Synaptic morphology1
Increased
 Electron microscopy
 2 months
Post-synaptic density size: inhibitory synapses1
Decreased
 Electron microscopy
 2 months
Neurotransmitter release: catecholamines1
Increased
 Fast scan voltammetry
 3-4 months
Decay kinetics of miniature post synaptic currents1
Abnormal
 Whole-cell patch clamp
 P17-22; p60-90
Neurotransmitter release: catecholamines1
Increased
 Fast scan voltammetry
 3-4 months
Self grooming: perseveration1
Increased
 Observation of repetitive behavior
 Adult
Allogrooming: perseveration1
Increased
 Observation of repetitive behavior
 0-3 weeks, adult
Sensorimotor gating1
Increased
 Prepulse inhibition
 Adult
Startle response: acoustic stimulus1
Increased
 NA
 Adult
Anxiety1
 No change
 Open field test
 Unreported
Anxiety1
 No change
 Elevated plus maze test
 Unreported
General locomotor activity1
 No change
 Elevated plus maze test
 Adult
General locomotor activity1
 No change
 Open field test
 Adult
Post-synaptic density size: excitatory synapses1
 No change
 Electron microscopy
 2 months
Synaptic neuroreceptors1
 No change
 Western blot
 2 months
Neurotransporter activity1
 No change
 Voltammogram measured dopamine concentrations over time
 3-4 months
Repetitive digging1
 No change
 Marble-burying test
 Adult
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Learning & memory, Maternal behavior, Molecular profile, Physiological parameters, Seizure, Social behavior





Download CNTNAP4's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
APBA1 Amyloid beta A4 precursor protein-binding family A member 1 320 Q02410 IP/WB
Spiegel I , et al. 2002
CASK calcium/calmodulin-dependent serine protein kinase (MAGUK family) 8573 O14936 IP/WB
Spiegel I , et al. 2002
FBXO21 F-box protein 21 23014 O94952 Y2H
Nakayama M , et al. 2002
MACF1 microtubule-actin crosslinking factor 1 23499 Q9UPN3 Y2H
Nakayama M , et al. 2002
MAST3 microtubule associated serine/threonine kinase 3 23031 O60307 Y2H
Nakayama M , et al. 2002
RANBP10 RAN binding protein 10 57610 Q6VN20 Y2H
Nakayama M , et al. 2002

RANBP10
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