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Relevance to Autism

Kang et al., 2017 demonstrated that VRK3-deficient mice exhibited hyperactivity, stereotyped behaviors, reduced social interaction, impaired context-dependent spatial memory, reduced dendritic spine number and arborization in the CA1 region of the hippocampus, and altered synaptic transmission; these phenotypes could be reversed by TrkB stimulation with 7,8-dihydroxyflavone.

Molecular Function

This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. In both human and mouse, this gene has substitutions at several residues within the ATP binding motifs that in other kinases have been shown to be required for catalysis. In vitro assays indicate the protein lacks phosphorylation activity. The protein, however, likely retains its substrate binding capability. This gene is widely expressed in human tissues and its protein localizes to the nucleus. Inactive kinase that suppresses ERK activity by promoting phosphatase activity of DUSP3 which specifically dephosphorylates and inactivates ERK in the nucleus.

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References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Autism-like behavior caused by deletion of vaccinia-related kinase 3 is improved by TrkB stimulation.

Rare

No Rare Variants Available

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
19
Duplication
 1
 
19
Deletion-Duplication
 18
 
19
Duplication
 1
 

Model Summary

VRK3 homozygous knockout mice exhibit hyperactivity, stereotypic behaviors, reduced social interaction, impaired context-dependent spatial memory, decrease in dendritic spine number and arborization in the hippocampus CA1 region, reduced rectification of AMPA receptormediated current, and altered expression of synaptic and signaling proteins, TrkB, Arc, and CaMKII. TrkB stimulation with 7,8-dihydroxyflavone reversed the autism-like behavior in VRK3-deficient mice (Kang MS, et al, J Exp Med. 2017).

References

Type
Title
Author, Year
Primary
Autism-like behavior caused by deletion of vaccinia-related kinase 3 is improved by TrkB stimulation.

M_VRK3_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Mice harboring a deletion encompassing exons 7 and 8 of VRK3 and a genetrap with the intron from engrailed 2 upstream of -galactosidase/neomycin resistance, -geo encoding gene.
Allele Type: knockout
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line:
Mutant ES Cell Line: YTA189
Model Source: BayGenomics

M_VRK3_2_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Mice harboring a deletion encompassing exons 7 and 8 of VRK3 and a genetrap with the intron from engrailed 2 upstream of -galactosidase/neomycin resistance, -geo encoding gene.
Allele Type: knockout
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line:
Mutant ES Cell Line: YTA189
Model Source: BayGenomics

M_VRK3_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity: ambulatory activity1
Increased
Description: Mutants show increase in total distance travelled on the open field compared to controls.
Exp Paradigm: NA
 Open field test
 Not reported
Neuroreceptor levels: glutamate receptors: nmda receptors1
Increased
Description: Mutants show increased expression of glun1 compared to controls.
Exp Paradigm: NA
 Western blot
 3 months
Dendritic architecture: dendritic length1
Increased
Description: Mutants show increase in length of dendritic spines in all spine types of the ca1 region compared to controls.
Exp Paradigm: NA
 Golgi-cox staining
 3.25 months
Neuroreceptor levels: glutamate receptors: ampa receptors1
Decreased
Description: Mutants show decrease in glua1 in whole cell lysates compared to controls.
Exp Paradigm: NA
 Western blot
 1, 3 months
Post-synaptic density size1
Decreased
Description: Mutants show reductions in psd length and thickness compared to controls.
Exp Paradigm: NA
 Electron microscopy
 3 months
Dendritic architecture: spine density1
Decreased
Description: Mutants show reductions in spine density in the ca1 and dentate gyrus regions with reductions in spine density in the ca1 more prominent on basal dendrites than apical dendrites.
Exp Paradigm: NA
 Golgi-cox staining
 3.25 months
Neuroreceptor levels: trkb1
Decreased
Description: Mutants show reduced levels of trkb compared to controls.
Exp Paradigm: NA
 Western blot
 3 months
Dendritic architecture: dendritic tree complexity1
Decreased
Description: Mutants show decreased dendritic arborization compared to controls.
Exp Paradigm: NA
 Sholl analysis
 3 months
Rectification of ion channels1
Decreased
Description: Mutants show decrease in the ratio of ampa receptormediated currents measured at 40 and 70 mv holding potentials (also known as rectification), compared to controls, indicating a decreased proportion of ca ion-permeable ampa receptor in mutants.
Exp Paradigm: NA
 Whole-cell patch clamp
 Not reported
Self grooming: perseveration1
Increased
Description: Mutants spend more time grooming compared to controls.
Exp Paradigm: NA
 Grooming behavior assessments
 Not reported
Social memory1
Decreased
Description: Mutant mice showed no preference for exploring the novel mouse over the familiar mouse compared to controls.
Exp Paradigm: NA
 Three-chamber social approach test
 Not reported
Social approach1
Decreased
Description: Mutant and control mice had no preference for the right or left chambers during the habituation period of the three-chamber test. mutant mice did not show any preference for exploring a novel mouse-containing cage over a novel empty cage in a three-chamber test, compared to controls.
Exp Paradigm: NA
 Three-chamber social approach test
 Not reported
Nest building behavior1
Decreased
Description: Mutant mice show reduced shredding of nest building materials compared to controls.
Exp Paradigm: Nesting was scored on a scale of 0 to 3 based on the extent to which the nesting material was converted into fine pieces.
 Nest building assay
 Not reported
Anxiety1
Decreased
Description: Mutants spend less time in the center of the field compared to controls.
Exp Paradigm: NA
 Open field test
 Not reported
Anxiety1
Decreased
Description: Mutants spend more time in the open arms compared to controls.
Exp Paradigm: NA
 Elevated plus maze test
 Not reported
Anxiety1
Decreased
Description: Mutants spend more time in the light than control mice.
Exp Paradigm: NA
 Light-dark exploration test
 Not reported
Cued or contextual fear conditioning: passive avoidance1
Increased
Description: Mutant mice show decrease in step-through latency compared to controls, after experiencing electric shock in a dark room. untrained mutant mice show no change in step-through latency compared to controls.
Exp Paradigm: NA
 Passive avoidance test
 Not reported
Spatial working memory1
Decreased
Description: Mutants mice had impaired spatial working memory compared with wt mice as indicated by increase in number of errors during the first 4 trial sessions on the barne's circular maze.
Exp Paradigm: NA
 Barnes maze test
 Not reported
Spatial reference memory1
Decreased
Description: Mutants mice had impaired spatial reference memory compared with wt mice as indicated by the decrease in the number of correct pokes during days 5 and 12 after training and the reduction in time spent at the target during probe trial when the escape hatch was removed.
Exp Paradigm: NA
 Barnes maze test
 Not reported
Object recognition memory1
Decreased
Description: Mutant mice exhibited a reduced ability to discriminate between familiar and novel objects at 24 h after training, compared to controls.
Exp Paradigm: NA
 Novel object recognition test
 Not reported
Maternal nurturing1
Decreased
Description: Mutant nursing females take longer times to retrieve their pups compared to controls.
Exp Paradigm: NA
 Pup retrieval assay
 Not reported
Targeted expression1
Decreased
Description: Mutants show absence of vrk3 protein and transcript compared to controls.
Exp Paradigm: Quantitative pcr (qrt-pcr)
 Quantitative pcr (qrt-pcr)
 Not reported
Protein localization: synapse1
Increased
Description: Mutants show increase in levels of arc and phosphorylated camkiialpha in the psd fraction compared to controls.
Exp Paradigm: NA
 Western blot
 1, 3 months
Protein phosphorylation1
Increased
Description: Mutants show increase in camkiialpha and erk phosphorylation, compared to controls. mutants show increase in phosphorylated-erk/erk ratio compared to controls.
Exp Paradigm: NA
 Western blot
 3 months
Protein expression level evidence1
Increased
Description: Mutants show increased levels ofsynaptic protein arc expression compared to controls.
Exp Paradigm: NA
 Western blot
 3 months
Protein phosphorylation1
Decreased
Description: Mutants show decreased mtor and s6k phosphorylation compared to controls.
Exp Paradigm: NA
 Western blot
 3 months
Protein expression level evidence1
Decreased
Description: Mutants show decreased expression of synaptic proteins syntaxin, pak3, and psd-95 compared to controls.
Exp Paradigm: NA
 Western blot
 3 months
Targeted expression1
Decreased
Description: Mutants show absence of vrk3 protein and transcript compared to controls.
Exp Paradigm: Western blot
 Western blot
 Not reported
Protein localization: synapse1
Decreased
Description: Mutants show reduced levels of psd-95 and phosphorylated trkb in the synaptosomal fractions compared to controls. mutants show a slight reduction in glua1 in the synaptosomal fraction compared to controls.
Exp Paradigm: NA
 Western blot
 1, 3 months
Exploratory activity1
 No change
 Barnes maze test
 Not reported
Protein expression level evidence1
 No change
 Western blot
 3 months
Protein localization: synapse1
 No change
 Western blot
 1, 3 months
General locomotor activity: ambulatory activity1
 No change
 Elevated plus maze test
 Not reported
Dendritic architecture: dendritic length1
 No change
 Golgi-cox staining
 3.25 months
Dendritic architecture: spine morphology1
 No change
 Golgi-cox staining
 3.25 months
Neuroreceptor levels: glutamate receptors: ampa receptors1
 No change
 Western blot
 3 months
Neuroreceptor levels: glutamate receptors: mglur1
 No change
 Western blot
 3 months
Neuroreceptor levels: glutamate receptors: nmda receptors1
 No change
 Western blot
 3 months
Action potential property: firing rate1
 No change
 Whole-cell patch clamp
 Not reported
Epsp-spike relationship1
 No change
 Whole-cell patch clamp
 Not reported
Miniature post synaptic current amplitude: excitatory1
 No change
 Whole-cell patch clamp
 Not reported
Miniature post synaptic current amplitude: inhibitory1
 No change
 Whole-cell patch clamp
 Not reported
Miniature post synaptic current frequency: excitatory1
 No change
 Whole-cell patch clamp
 Not reported
Miniature post synaptic current frequency: inhibitory1
 No change
 Whole-cell patch clamp
 Not reported
Neurotransmitter release1
 No change
 Whole-cell patch clamp
 Not reported
Presynaptic function: paired-pulse facilitation1
 No change
 Whole-cell patch clamp
 Not reported
Spontaneous post synaptic event amplitude: excitatory currents1
 No change
 Whole-cell patch clamp
 Not reported
Spontaneous post synaptic event amplitude: inhibitory currents1
 No change
 Whole-cell patch clamp
 Not reported
Spontaneous post synaptic event frequency: excitatory currents1
 No change
 Whole-cell patch clamp
 Not reported
Spontaneous post synaptic event frequency: inhibitory currents1
 No change
 Whole-cell patch clamp
 Not reported
Synaptic neuroreceptor ratio (nmdar/ampar) dependent transmission1
 No change
 Whole-cell patch clamp
 Not reported
Synaptic plasticity: hippocampal ltd1
 No change
 Whole-cell patch clamp
 Not reported
Synaptic plasticity: hippocampal ltp1
 No change
 Whole-cell patch clamp
 Not reported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Physiological parameters, Seizure, Sensory

M_VRK3_2_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity: ambulatory activity1
Increased
Description: Mutants show increase in total distance travelled on the open field compared to controls.
Exp Paradigm: NA
 Open field test
 Not reported
Anxiety1
Decreased
Description: Mutants spend less time in the center of the field compared to controls.
Exp Paradigm: NA
 Open field test
 Not reported
Anxiety1
Decreased
Description: Mutants spend more time in the light than control mice.
Exp Paradigm: NA
 Light-dark exploration test
 Not reported
Spatial reference memory1
Decreased
Description: Mutants mice had impaired spatial reference memory compared with wt mice as indicated by the decrease in the number of correct pokes during days 5 and 12 after training and the reduction in time spent at the target during probe trial when the escape hatch was removed.
Exp Paradigm: NA
 Barnes maze test
 Not reported
Object recognition memory1
Decreased
Description: Mutant mice exhibited a reduced ability to discriminate between familiar and novel objects at 24 h after training, compared to controls.
Exp Paradigm: NA
 Novel object recognition test
 Not reported
Spatial working memory1
Decreased
Description: Mutants mice had impaired spatial working memory compared with wt mice as indicated by increase in number of errors during the first 4 trial sessions on the barne's circular maze.
Exp Paradigm: NA
 Barnes maze test
 Not reported
Exploratory activity1
 No change
 Barnes maze test
 Not reported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Immune response, Maternal behavior, Molecular profile, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

No PIN Data Available
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