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 ...
294 cases (254 male, 40 female) with diagnosis of Asperger syndrome (DSM-IV or ICD-10 criteria) and 318 controls (250 male, 68 female), all of Caucasian ancestry
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)
Description: Late-middle aged Dock4 mutant mice exhibited no difference in the number of mature neurons in the CA1 and CA3 region of the hippocampus, but a significantly decreased number of mature neurons in the dentate gyrus.
Exp Paradigm: NeuN
Description: Late-middle aged Dock4 mutant mice displayed a similar number of cells in the CA3 and dentate gyrus region of the hippocampus, but significantly decreased numbers of Nissl-positive cells in the CA1 region, suggesting that Dock4 deficiency leads to a reduced number of hippocampal CA1 neurons in late-middle age.
Exp Paradigm: Nissl-staining
Description: Late-middle aged Dock4 mutant mice exhibited no difference in astrocyte number in the CA1 and CA3 region of the hippocampus, but a significantly decreased astrocyte number in the dentate gyrus.
Exp Paradigm: GFAP
Description: Late-middle aged Dock4 mutant mice exhibited a significantly decreased oligodendrocyte number in the CA1, CA3, and dentate gyrus region of the hippocampus compared to wildtype controls.
Exp Paradigm: Oligo2
Description: In the social novelty phase, adult and late-middle aged wildtype littermates exhibited a preference for exploring the new mouse (S2) over the familiar (S1) one, whereas adult Dock4 mutant mice failed to distinguish the two subjects. A 10-min interval was introduced after the social novelty phase to allow for memory formation. Then, a familiar mouse (S1) was placed with another new mouse (S3) to test social memory ability. Adult and late-middle aged Dock4 KO mice displayed social memory deficit, displaying no significant preference for the new mouse compared to the familiar mouse.
Description: Late-middle aged Dock4 mutant mice displayed a significant increase in duration of time spent in the center (%), a significant decrease in velocity in the center (mm/s), and no change in frequency to center or distance traveled in the center (m). Mutant mice also displayed a significant decrease in duration in the outer portion (%), a decrease in distance traveled in the outer portion (m) (p= 0.063), and no change in velocity in the outer portion (mm/s) compared to wildtype controls.
Description: Dock4 mutant mice exhibited significant decreases in the total distance traveled, duration (%) in open sections, and distance traveled in open sections. Mutant mice also displayed slightly decreased travel distance and velocity in closed sections compared to wildtype controls. Mutant mice displayed similar entry times and velocity in the open sections compared to wildtype controls.
Description: The hippocampus of late-middle aged Dock4 mutant mice expressed similar protein levels of IL6 and IL1-beta, but significantly decreased TNF-alpha protein expression compared to wildtype controls.
Exp Paradigm: IL6, IL1-beta, TNF-alpha
Description: Late-middle aged Dock4 mutant mice exhibited decreased memory during the probe test compared to wildtype controls, spending more time to locate the target hole and fewer number of entries to the target hole. Additionally, mutant mice exhibited impaired discrimination between the target quadrant and the opposite quadrant, spending less time in the target region.
Exp Paradigm: Probe test: 24 hours after initial 5-day training
Description: While adult and late-middle aged wildtype mice spent more time on the object placed in the new location, Dock4 mutant mice failed to show this same preference, spending less time with the newly-placed object.
