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Relevance to Autism

Assocation between the DOCK4 gene and ASD has been observed in two studies (Maestrini et al., 2010; Liang et al., 2014). Deletions involving the DOCK4 gene has also been implicated in ASD and dyslexia (Maestrini et al., 2010; Pagnamenta et al., 2010).

Molecular Function

Involved in regulation of adherens junction between cells. Plays a role in cell migration. Functions as a guanine nucleotide exchange factor (GEF), which activates Rap1 small GTPase by exchanging bound GDP for free GTP.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism ...
ASD
Positive Association
A Pooled Genome-Wide Association Study of Asperger Syndrome.
ASD
Asperger syndrome
Positive Association
Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population.
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
Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia.
Dyslexia
Support
Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly
DD
ASD or autistic features, ADHD, ID, epilepsy/seizu
Support
Integrating de novo and inherited variants in 42
ASD
Support
Deficiency of Autism-Related Gene Dock4 Leads to Impaired Spatial Memory and Hippocampal Function in Mice at Late Middle Age
ASD
Support
Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function.
Recent Recommendation
The atypical guanine nucleotide exchange factor Dock4 regulates neurite differentiation through modulation of Rac1 GTPase and actin dynamics.
Recent Recommendation
Rac GEF Dock4 interacts with cortactin to regulate dendritic spine formation.
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN603R001 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN603R002 
 copy_number_gain 
  
  
 Familial 
 Paternal 
 Multiplex 
 GEN603R003 
 initiator_codon_variant 
 G>A 
 p.Met1Ile 
 Familial 
 Maternal 
 Multiplex 
 GEN603R004 
 missense_variant 
 c.4250G>A 
 p.Arg1417His 
 De novo 
  
 Simplex 
 GEN603R005 
 synonymous_variant 
 c.4962A>G 
 p.Val1654= 
 De novo 
  
 Simplex 
 GEN603R006 
 synonymous_variant 
 c.3477A>G 
 p.Ser1159%3D 
 De novo 
  
  
 GEN603R007 
 missense_variant 
 c.1442G>A 
 p.Arg481Gln 
 De novo 
  
 Simplex 
 GEN603R008 
 missense_variant 
 c.4832A>G 
 p.His1611Arg 
 De novo 
  
  
 GEN603R009 
 missense_variant 
 c.832A>G 
 p.Ile278Val 
 De novo 
  
  
 GEN603R010 
 missense_variant 
 c.2945C>T 
 p.Thr982Ile 
 De novo 
  
 Simplex 
 GEN603R011a 
 missense_variant 
 c.3131T>C 
 p.Met1044Thr 
 De novo 
  
 Simplex 
 GEN603R011b 
 missense_variant 
 c.758C>T 
 p.Pro253Leu 
 Familial 
 Paternal 
 Simplex 
 GEN603R012 
 missense_variant 
 c.3200T>C 
 p.Ile1067Thr 
 De novo 
  
 Simplex 
 GEN603R013 
 missense_variant 
 c.5913G>T 
 p.Lys1971Asn 
 Unknown 
  
 Simplex 
 GEN603R014 
 stop_gained 
 c.892C>T 
 p.Arg298Ter 
 Familial 
 Maternal 
 Simplex 
 GEN603R015 
 stop_gained 
 c.2770C>T 
 p.Arg924Ter 
 Unknown 
 Not maternal 
 Multiplex 
 GEN603R016 
 frameshift_variant 
 c.3937del 
 p.Asp1313ThrfsTer27 
 Familial 
 Maternal 
 Simplex 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
7
Deletion
 2
 
7
Deletion-Duplication
 28
 
7
Deletion
 1
 
7
Deletion-Duplication
 45
 
7
Deletion
 3
 

Model Summary

Dock4 knockout mice show age-dependent deficits in locomotion, anxiety and spatial memory, as well as a non-age dependent deficit in social memory. Knockout mice show abnormal hippocampal morphology with reduced number of neurons and oligodendrocytes in the dentate gyrus region of the hippocampus.

References

Type
Title
Author, Year
Primary
Deficiency of Autism-Related Gene Dock4 Leads to Impaired Spatial Memory and Hippocampal Function in Mice at Late Middle Age
Model Type: Genetic
Model Genotype: Homozygous
Mutation: Dock4 knockout mice (MGI:6850050) were generated using a standard strategy of Cre-LoxP recombination. The targeting vector contained Exon 3 of a Dock4 homology region, covering 5.4 kb upstream and 4.2 kb downstream of Exon 3. An FRT-flanked Neo cassette was inserted 3' of Exon 3, and two LoxP sites were introduced 5' of Exon 3 and 3' of Neo, respectively. F1 mice carrying the Neo-floxed Dock4 allele (Dock4flox-neo) were crossed with Flp mice (C57BL/6 background) to remove the Neo cassette to obtain Dock4 floxed mice (Dock4flox mice). Alternatively, Dock4flox-neo/+ mice were crossed with EIIa-Cre germline deleter mice (C57BL/6 background) to obtain Dock4+/+ (wildtype), Dock4+/- (heterozygous) and Dock4-/- (knockout) mice.
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: C57BL/6J
ES Cell Line: Not Specified
Mutant ES Cell Line:
Model Source: Biocytogen (PMID 31388105)
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity: ambulatory activity1
Decreased
 Open field test
 15-17 months
Hippocampal morphology1
Abnormal
 Histology
 15-17 months
Astrocyte number1
Decreased
 Immunofluorescence staining
 15-17 months
Number of oligodendrocytes1
Decreased
 Immunofluorescence staining
 15-17 months
Neuronal number1
Decreased
 Immunofluorescence staining
 15-17 months
Head bobbing1
Increased
 Elevated zero maze test
 15-17 months
Social memory1
Decreased
 Three-chamber social approach test
 4-6 months, 15-17 months
Anxiety1
Increased
 Elevated zero maze test
 15-17 months
Anxiety1
Decreased
 Open field test
 15-17 months
Cytokine levels: pro-inflammatory1
Decreased
 Western blot
 15-17 months
Object recognition memory1
Decreased
 Object-place recognition test
 4-6 months, 15-17 months
Spatial reference memory1
Decreased
 Barnes maze test
 15-17 months
Anxiety1
 No change
 Open field test
 4-6 months
Object recognition memory1
 No change
 Novel object recognition test
 15-17 months
Spatial learning1
 No change
 Barnes maze test
 4-6 months, 15-17 months
Spatial reference memory1
 No change
 Barnes maze test
 4-6 months
General locomotor activity: ambulatory activity1
 No change
 Barnes maze test
 4-6 months, 15-17 months
General locomotor activity: ambulatory activity1
 No change
 Open field test
 4-6 months
Brain size1
 No change
 Histology
 4-6 months, 15-17 months
Hippocampal morphology1
 No change
 Histology
 4-6 months
Microglial number1
 No change
 Immunofluorescence staining
 15-17 months
Social approach1
 No change
 Three-chamber social approach test
 4-6 months, 15-17 months
 Not Reported:





Download DOCK4's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
ARRB1 arrestin, beta 1 408 P49407 IP; LC-MS/MS
Huttlin EL , et al. 2015
DOCK9 dedicator of cytokinesis 9 23348 Q9BZ29 IP; LC-MS/MS; IP/WB
Abraham S , et al. 2015
ELMO1 engulfment and cell motility 1 9844 Q92556 in vitro binding assay
Abraham S , et al. 2015
ELMO1 engulfment and cell motility 1 9844 Q92556 IP; LC-MS/MS
Huttlin EL , et al. 2015
ELMO3 Engulfment and cell motility protein 3 79767 Q96BJ8-2 IP; LC-MS/MS
Huttlin EL , et al. 2015
ERMAP Erythroid membrane-associated protein 114625 Q96PL5 IP; LC-MS/MS
Huttlin EL , et al. 2015
GRB2 growth factor receptor-bound protein 2 2885 P62993 IP; LC-MS/MS
Huttlin EL , et al. 2015
STAT1 signal transducer and activator of transcription 1, 91kDa 6772 P42224 IP; LC-MS/MS
Huttlin EL , et al. 2015
VSIG8 V-set and immunoglobulin domain-containing protein 8 284677 Q5VU13 IP; LC-MS/MS
Huttlin EL , et al. 2015

ELMO3
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