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Relevance to Autism

A de novo frameshift variant in DVL3 was observed in an ASD proband from the Simons Simplex Collection (Dong et al., 2014). More recently, a Dvl1/Dvl3+/ mouse model was shown to display adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation, phenotypes which could be rescued by pharmacological activation of the canonical Wnt pathway (Belinson et al., 2016).

Molecular Function

This gene is a member of a multi-gene family which shares strong similarity with the Drosophila dishevelled gene, dsh. The Drosophila dishevelled gene encodes a cytoplasmic phosphoprotein that regulates cell proliferation.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder.
ASD
Recent Recommendation
ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size.
Recent Recommendation
Prenatal -catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN797R001 
 frameshift_variant 
 c.1618dup 
 p.Tyr540LeufsTer42 
 De novo 
 NA 
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
3
Duplication
 1
 
3
Duplication
 2
 
3
Duplication
 1
 
3
Duplication
 2
 
3
Duplication
 1
 
3
Duplication
 1
 
3
Deletion
 1
 
3
Deletion
 2
 
3
Deletion
 7
 

Model Summary

Dvl3 null embryos die perinatally whereas Dvl3 het mice survive displaying mild deficits in neuronal differentiation.

References

Type
Title
Author, Year
Additional
Prenatal -catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.
Primary
Prenatal -catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.

M_DVL1_2_KO_HM_DVL3_DM

Model Type: Genetic
Model Genotype: Double mutant
Mutation: Dvl 1 null mice were crossed with Dvl 3het mice, with the offspring further crossed with Dvl 1 null mice to obtain the double mutant: Dvl1-/- 3+/- ( homozygous for Dvl1 knockout and heterozygous for Dvl3).
Allele Type: Targeted(double knockout)
Strain of Origin: 129S6/SvEvTac
Genetic Background: 129S6
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_DVL1_2_KO_HM_DVL3_DM_BETAGAL

Model Type: Genetic
Model Genotype: Double mutant
Mutation: BAT gal mice transgenic mice (on 129), a reporter strain that expresses beta-galactosidase in the presence of activated beta-catenin, were crossed with Dvl1 mutants to generate BAT-gal Dvl mutant mice to test the beta catenin expression in these mutants.
Allele Type: Targeted( double knockout); Reporter
Strain of Origin: 129S6/SvEvTac
Genetic Background: 129S6
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_DVL1_2_KO_HM_DVL3_DM_BRDU

Model Type: Genetic
Model Genotype: Double mutant
Mutation: Dvl1-/- 3+/- double mutant pregnant dams i.p. injected with Brdu at 40 microg per gram mouse weight 60 min prior to embryo collection to identify proliferating cells.
Allele Type: Targeted(double knockout); Marker
Strain of Origin: 129S6/SvEvTac
Genetic Background: 129S6
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_DVL3_1_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: A genomic fragment spanning from part of exon 2 through exon 7 was replaced with a neo cassette.
Allele Type: Targeted(knockout)
Strain of Origin: 129S6/SvEvTac
Genetic Background: 129S6
ES Cell Line: TC1
Mutant ES Cell Line:
Model Source: JAX

M_DVL1_2_KO_HM_DVL3_DM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Brain size1
Increased
Description: There is a transient, but significant, increase in brain weight at E14.5 in Dvl DMs
 Histology
 E14.5
Cortical lamination1
Decreased
Description: Expression of layer 2-3 marker Pou3f2 is reduced by E18.5 in Dvl DMs
 Immunohistochemistry
 E18.5
Cortical lamination1
Decreased
Description: Expression of deep layer markers (layer 6) like Ctip2, Foxp2 and Pou3f2 is reduced by E18.5 in Dvl DMs
 Immunohistochemistry
 E18.5
Neuronal differentiation and specification in the brain1
Decreased
Description: Neuronal precursors expressing markers Sox2+ Tbr2+ were increased compared to WT controls whereas Sox2 alone were decreased indicating impaired neuronal differentiation in Dvl DMs, , the difference is observed transiently at E14.5
 Immunohistochemistry
 E14.5
Cell proliferation: neural precursors1
Increased
Description: Increased number of mitotic cells are observed in apical and basal profenitor regions of cortex in Dvl DMs
 Immunohistochemistry
 E14.5
Cortical thickness1
Increased
Description: There is a transient, but significant, increase in dorsoventral thickness of the cortical plate at E14.5, it is noted that the ventricular zone is not different in width even at E14.5
 Histology
 E14.5
Repetitive digging1
Increased
Description: Dvl DMs bury significantly larger number of marbles than WT controls or Dvl1 null mutants
 Marble-burying test
 
Allogrooming: perseveration1
Increased
Description: Dvl DMs exhibit significantly increased allogrooming (whisker trimming)
 Grooming behavior assessments
 >6 weeks
Social approach1
Decreased
Description: Dvl DMs display no preference for social stimulus mouse over an object, unlike WT controls
 Three-chamber social approach test
 >6 weeks
Nest building behavior1
Decreased
Description: Dvl DMs display decreased depth of nests built compared to WT controls
 Nest building assay
 
Protein-dna complex assembly1
Decreased
Description: Dvl DMs have reduced enrichment for Pou3f2 (Brn2) binding sites on Tbr2 as well as of Beta catenin interaction with Pou3f2 and Axin2 promoters
 Chromatin immunoprecipitation sequencing (chip-seq)
 E14.5
Protein expression level evidence1
Decreased
Description: Dishevelled double mutants (DMs) have decreased levels of Pou3f2 in the cortex
 Western blot
 E14.5
Mortality/lethality1
 No change
 Survival analysis
 
Anxiety1
 No change
 Open field test
 >6 weeks
General locomotor activity1
 No change
 Open field test
 >6 weeks
Postural reflex1
 No change
 
 3.8 months
Brain size1
 No change
 Histology
 E12.5, E16.5, E18.5, E21.5
Cortical lamination1
 No change
 Immunohistochemistry
 E18.5
Cortical thickness1
 No change
 Histology
 E12.5, E16.5, E18.5, E21.5
Neuronal differentiation and specification in the brain1
 No change
 Immunohistochemistry
 E12.5, E13.5, E16.5, E18.5
Reproductive function1
 No change
 General observations
 Adult
Self grooming: perseveration1
 No change
 Grooming behavior assessments
 3.8 months
Ear twitch reflex or preyer's reflex1
 No change
 
 >6 weeks
Sensorimotor gating1
 No change
 Prepulse inhibition
 >6 weeks
Startle response: acoustic stimulus1
 No change
 Acoustic startle reflex test
 >6 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Immune response, Learning & memory, Maternal behavior, Neurophysiology, Physiological parameters, Seizure

M_DVL1_2_KO_HM_DVL3_DM_BETAGAL

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Signaling1
Decreased
Description: Beta-galactosidase staining is decreased in the cortical sections of Dvl DM emryos indicating decrease in beta-catenin transcription
 Immunohistochemistry
 E14.5
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_DVL1_2_KO_HM_DVL3_DM_BRDU

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Cell proliferation: neural precursors1
Increased
Description: Dvl DMs have increased number of Ki67+ and BrdU + cells in the brain
 Immunohistochemistry
 E14.5
 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

M_DVL3_1_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuronal differentiation and specification in the brain1
Decreased
Description: Dvl3 hets have impaired neuronal differentiation indicated by a transient increase in Sox2+Tbr2+ neural precursors similar to other Dvl mutants, transiently at E14.5
 Immunohistochemistry
 E14.5
Brain size1
 No change
 Histology
 E12.5, E14.5,E16.5,E18.5, P0
Cortical thickness1
 No change
 Histology
 E12.5, E13.5, E14.5, E16.5, E18.5, E21.5
Neuronal differentiation and specification in the brain1
 No change
 Immunohistochemistry
 E12.5, E13.5, E16.5, E18.5
 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
AQR aquarius homolog (mouse) 9716 O60306 IP; LC-MS/MS
Huttlin EL , et al. 2015
CCDC12 coiled-coil domain containing 12 151903 J3KR35 IP; LC-MS/MS
Huttlin EL , et al. 2015
CDC5L CDC5 cell division cycle 5-like (S. pombe) 988 Q99459 IP; LC-MS/MS
Huttlin EL , et al. 2015
CRNKL1 crooked neck pre-mRNA splicing factor-like 1 (Drosophila) 51340 Q9BZJ0 IP; LC-MS/MS
Huttlin EL , et al. 2015
CSNK1D casein kinase 1, delta 1453 P48730 Y2H
Rual JF , et al. 2005
CSNK1D casein kinase 1, delta 1453 P48730 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
CSNK2A1 casein kinase 2, alpha 1 polypeptide 1457 P68400 IP; LC-MS/MS
Huttlin EL , et al. 2015
DRD2 dopamine receptor D2 1813 P14416 IP/WB
Sutton LP and Rushlow WJ 2011
DVL2 dishevelled, dsh homolog 2 (Drosophila) 1856 O14641 IP; LC-MS/MS
Huttlin EL , et al. 2015
FOXK1 forkhead box K1 221937 P85037 IP; LC-MS/MS
Huttlin EL , et al. 2015
FOXK2 forkhead box K2 3607 Q01167 IP; LC-MS/MS
Huttlin EL , et al. 2015
ISY1 ISY1 splicing factor homolog (S. cerevisiae) 57461 Q9ULR0 IP; LC-MS/MS
Huttlin EL , et al. 2015
MBD1 methyl-CpG binding domain protein 1 4152 Q9UIS9 Y2H
Sakai Y , et al. 2011
NXF2 Nuclear RNA export factor 2 56001 Q9GZY0 IP; LC-MS/MS
Huttlin EL , et al. 2015
NXN nucleoredoxin 64359 Q6DKJ4 IP; LC-MS/MS
Huttlin EL , et al. 2015
OBSL1 obscurin-like 1 23363 O75147 IP; LC-MS/MS
Huttlin EL , et al. 2015
PCBP3 poly(rC) binding protein 3 54039 P57721 IP; LC-MS/MS
Huttlin EL , et al. 2015
PITX1 paired-like homeodomain 1 5307 P78337 Y2H
Rual JF , et al. 2005
PPIE peptidylprolyl isomerase E (cyclophilin E) 10450 Q3S611 IP; LC-MS/MS
Huttlin EL , et al. 2015
PTEN phosphatase and tensin homolog 5728 F6KD01 LUMIER with BACON; IP/WB
Shnitsar I , et al. 2015
RACK1 receptor for activated C kinase 1 10399 P63244 IP/WB
Cheng M , et al. 2016
SNW1 SNW domain containing 1 22938 Q13573 IP; LC-MS/MS
Huttlin EL , et al. 2015
SYF2 SYF2 homolog, RNA splicing factor (S. cerevisiae) 25949 O95926 IP; LC-MS/MS
Huttlin EL , et al. 2015
VANGL1 VANGL planar cell polarity protein 1 81839 Q8TAA9 IP; LC-MS/MS
Huttlin EL , et al. 2015
VANGL2 Vang-like protein 2 57216 Q9ULK5 IP; LC-MS/MS
Huttlin EL , et al. 2015
WDR83 WD repeat domain 83 84292 Q9BRX9 IP; LC-MS/MS
Huttlin EL , et al. 2015
XAB2 XPA binding protein 2 56949 Q9HCS7 IP; LC-MS/MS
Huttlin EL , et al. 2015

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