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Relevance to Autism

Two de novo loss-of-function variants in the DIP2A gene have been identified in ASD probands from the Simons Simplex Collection (refs).

Molecular Function

The protein encoded by this gene may be involved in axon patterning in the central nervous system.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo gene disruptions in children on the autistic spectrum.
ASD
Support
Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin.
ASD
Support
Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
ASD
Support
Dysregulation of AMPK-mTOR signaling leads to comorbid anxiety in Dip2a KO mice
ASD
Anxiety
Support
De novo genic mutations among a Chinese autism spectrum disorder cohort.
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Support
Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.
ASD
Support
Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder
ASD
Support
Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.
ASD
Support
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
ASD
Support
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD
Recent Recommendation
The contribution of de novo coding mutations to autism spectrum disorder
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN644R001 
 frameshift_variant 
 c.1643_1644insCTGGTCT 
 p.Glu549TrpfsTer3 
 De novo 
  
 Simplex 
 GEN644R002 
 stop_gained 
 c.1775G>A 
 p.Trp592Ter 
 De novo 
  
 Simplex 
 GEN644R003 
 missense_variant 
 c.1505G>A 
 p.Gly502Asp 
 Familial 
 Maternal 
  
 GEN644R004 
 missense_variant 
 c.1697G>A 
 p.Gly566Asp 
 Familial 
 Paternal 
  
 GEN644R005 
 missense_variant 
 c.3997G>A 
 p.Val1333Ile 
 Familial 
 Paternal 
 Simplex 
 GEN644R006 
 missense_variant 
 c.2716G>A 
 p.Gly906Arg 
 Familial 
 Paternal 
 Simplex 
 GEN644R007 
 missense_variant 
 c.2758G>A 
 p.Gly920Arg 
 Unknown 
 Not maternal 
 Simplex 
 GEN644R008 
 missense_variant 
  
  
 De novo 
  
 Simplex 
 GEN644R009 
 synonymous_variant 
  
  
 De novo 
  
 Simplex 
 GEN644R010 
 splice_region_variant 
 c.2445+6C>T 
  
 De novo 
  
 Simplex 
 GEN644R011 
 intron_variant 
 c.3197-41A>G 
  
 De novo 
  
 Simplex 
 GEN644R012 
 splice_site_variant 
 c.1300+2T>G 
  
 Familial 
 Maternal 
 Simplex 
 GEN644R013 
 splice_site_variant 
 c.3501+2T>C 
  
 Unknown 
  
  
 GEN644R014 
 missense_variant 
 c.4202A>C 
 p.Tyr1401Ser 
 Unknown 
  
  
 GEN644R015 
 missense_variant 
 c.260C>T 
 p.Ser87Leu 
 De novo 
  
 Multiplex 
 GEN644R016 
 missense_variant 
 c.3262G>A 
 p.Val1088Ile 
 De novo 
  
 Simplex 
 GEN644R017 
 splice_region_variant 
 c.2953-6G>A 
  
 De novo 
  
  
 GEN644R018 
 missense_variant 
 c.3427G>A 
 p.Asp1143Asn 
 De novo 
  
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
21
Duplication
 3
 
21
Duplication
 11
 
21
Duplication
 2
 
21
Deletion-Duplication
 1
 
21
Deletion
 2
 
21
Deletion
 3
 
21
Deletion
 5
 
21
Deletion-Duplication
 43
 

Model Summary

Mice with Dip2a deletion show defects in spine morphogenesis, thin postsynaptic density, reduced synaptic transmission of pyramidal neurons, excessive self-grooming, defects in social novelty, and decreased levels of acetylated cortactin. Acetylation mimetic cortactin restores the impaired synaptic transmission and ameliorated repetitive behaviors in these mutants.

References

Type
Title
Author, Year
Primary
Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin.

M_DIP2A_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: CRISPR/Cas9 technology replaced 65 kb downstream of exon 1 with an FRT-flanked neomycin resistance cassette with a 3' loxP site. Founders 3 (64,901 bp), 5 (64,918 bp) and 13 (64,918 bp) transmitted germline. To visualize spines, Dip2a knockout KO mice were crossed with Thy1 GFP mice to label neurons randomly with GFP in the cortex, hippocampus, and amygdala.
Allele Type: Knockout
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line:
Mutant ES Cell Line:
Model Source: PMID 25803037 (Zhang et al, 2015)

M_DIP2A_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Self grooming: home cage/familiar environment1
Increased
Description: Mutants show increase in self grooming in the home cage.
Exp Paradigm: NA
 Home cage behavior
 6-8 weeks
Post-synaptic density size1
Decreased
Description: Mutants show stubby and flattened postsynaptic density structure.
Exp Paradigm: NA
 Transmission electron microscopy (tem)
 P56
Dendritic architecture: spine density1
Increased
Description: Mutants show increase in basal spine density in the external and internal pyramidal layers of the cerebral cortex but show no change in apical spine density in the same layers.
Exp Paradigm: NA
 Confocal microscopy
 P56
Neuroreceptor levels: glutamate receptors: nmda receptors1
Decreased
Description: Mutants show decrease in nr1, nr2a, and nr2b in the psd fraction but no change in nmda neuroreceptor subunits nr1, nr2a, and nr2b in total cortical lysates.
Exp Paradigm: NA
 Western blot
 P56
Neuroreceptor levels: glutamate receptors: ampa receptors1
Decreased
Description: Mutants show decrease in glur1 in the psd fraction but no change in ampa neuroreceptor subunits glur1 and glur2 in total cortical lysates.
Exp Paradigm: NA
 Western blot
 P56
Dendritic architecture: spine morphology1
Abnormal
Description: Mutants show a decrease in the proportion of mushroom-like spines in basal dendrites in the internal and external layers of the cerebral cortex but no change in the morphology of the apical spines. mutants show increase in stubby spines in basal dendrites with a significant increase in spine head width and a decrease in spine length.
Exp Paradigm: NA
 Confocal microscopy
 P56
Spontaneous post synaptic event amplitude: excitatory currents1
Decreased
Description: Mutants show decrease in the amplitude of spontaneous excitatory postsynaptic current (sepsc) in the internal pyramidal layer of the cerebral cortex.
Exp Paradigm: NA
 Whole-cell voltage clamp
 P56
Self grooming: perseveration1
Increased
Description: Mutants show increase in total time spent self-grooming but no change in frequency of self-grooming.
Exp Paradigm: NA
 Open field test
 6-8 weeks
Repetitive digging1
Increased
Description: Mutants bury more marbles.
Exp Paradigm: NA
 Marble-burying test
 6-8 weeks
Social memory1
Decreased
Description: Mutants show no preference for unfamiliar over familiar mouse.
Exp Paradigm: NA
 Three-chamber social approach test
 6-8 weeks
Ultrasonic vocalization: isolation induced1
Decreased
Description: Mutants show reduced call duration and calling time.
Exp Paradigm: NA
 Monitoring ultrasonic vocalizations
 P4
Targeted expression1
Decreased
Description: Mutants show decrease in dip2a protein expression in the brain.
Exp Paradigm: NA
 Western blot
 P56
Protein modification process1
Decreased
Description: Mutants show decrease in levels of acetylated cortactin in the cerebral cortex but no change in levels of total cortactin or phosphorylated cortactin.
Exp Paradigm: NA
 Western blot
 P56
Metabolite levels: neurometabolites1
Decreased
Description: Mutants show a decrease in the levels of acetyl coenzymea in the brain lysate.
Exp Paradigm: NA
 Western blot
 P56
Targeted expression1
Decreased
Description: Mutants show decrease in dip2a transcript levels in the hippocampus, cerebral cortex, thalamus and cerebellum.
Exp Paradigm: NA
 Quantitative pcr (qrt-pcr)
 P56
General characteristics1
 No change
 General observations
 P56
Size/growth1
 No change
 Body weight measurement
 P56, p0-70
Object recognition memory1
 No change
 Novel object recognition test
 6-8 weeks
Chromatin modification: histone acetylation1
 No change
 Western blot
 P56
Enzyme activity1
 No change
 Western blot
 P56
Protein expression level evidence1
 No change
 Western blot
 P56
General locomotor activity1
 No change
 Open field test
 6-8 weeks
General locomotor activity: ambulatory activity1
 No change
 Open field test
 6-8 weeks
Brain morphology1
 No change
 Histology
 P56
Brain morphology1
 No change
 Gross necroscopy
 P56
Brain size1
 No change
 Measurement of tissue weight
 P56
Cortical lamination1
 No change
 Histology
 P56
Neuronal number1
 No change
 Histology
 P56
Spontaneous post synaptic event frequency: excitatory currents1
 No change
 Whole-cell voltage clamp
 P56
Reproductive function1
 No change
 Histology
 P56
Olfaction1
 No change
 Buried food test
 6-8 weeks
Rearing behavior1
 No change
 Open field test
 6-8 weeks
Social approach1
 No change
 Three-chamber social approach test
 6-8 weeks
 Not Reported: Circadian sleep/wake cycle, Emotion, Immune response, Maternal behavior, Physiological parameters, Seizure





Download DIP2A's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
ADAMTSL4 ATP10A 54507 Q6UY14 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
AES amino-terminal enhancer of split 166 Q08117 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
C1ORF186 Uncharacterized protein C1orf186 440712 Q6ZWK4 IP; LC-MS/MS
Huttlin EL , et al. 2015
C20orf20 MRG/MORF4L binding protein 55257 A8C4L5 IP/WB
Sardiu ME , et al. 2008
CCDC33 coiled-coil domain containing 33 80125 Q8N5R6 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
CEP44 centrosomal protein 44kDa 80817 Q9C0F1 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
EFNB2 ephrin-B2 1948 P52799 IP; LC-MS/MS
Huttlin EL , et al. 2015
FAM214B family with sequence similarity 214, member B 80256 Q7L5A3 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
GPATCH2L G patch domain containing 2-like 55668 Q9NWQ4 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
HAVCR2 Hepatitis A virus cellular receptor 2 84868 Q8TDQ0 IP; LC-MS/MS
Huttlin EL , et al. 2015
IL20RA Interleukin-20 receptor subunit alpha 53832 Q9UHF4 IP; LC-MS/MS
Huttlin EL , et al. 2015
JMJD6 jumonji domain containing 6 23210 Q6NYC1 Y2H-seq; in vitro methylation assay; LC-MS/MS
Weimann M , et al. 2013
LPCAT1 lysophosphatidylcholine acyltransferase 1 79888 Q8NF37 IP; LC-MS/MS
Huttlin EL , et al. 2015
MBIP MAP3K12 binding inhibitory protein 1 51562 Q9NS73 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
PSME3 proteasome (prosome, macropain) activator subunit 3 (PA28 gamma; Ki) 10197 P61289 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
PTGER3 prostaglandin E receptor 3 (subtype EP3) 5733 P43115 IP; LC-MS/MS
Huttlin EL , et al. 2015
PTPN3 protein tyrosine phosphatase, non-receptor type 3 5774 B7Z9V1 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
SELE E-selectin 6401 P16581 IP; LC-MS/MS
Huttlin EL , et al. 2015
SORBS3 sorbin and SH3 domain containing 3 10174 O60504 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
SSSCA1 Sjogren syndrome/scleroderma autoantigen 1 10534 O60232 IP; LC-MS/MS
Huttlin EL , et al. 2015
STAC3 SH3 and cysteine rich domain 3 246329 Q96MF2 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
THBS3 Thrombospondin-3 7059 P49746 IP; LC-MS/MS
Huttlin EL , et al. 2015
TMCC2 transmembrane and coiled-coil domain family 2 NM_014858 O75069 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
TOP3B topoisomerase (DNA) III beta 8940 O95985 HITS-CLIP
Xu D , et al. 2013
TPCN2 two pore segment channel 2 219931 Q59G56 IP; LC-MS/MS
Huttlin EL , et al. 2015
TRIM39 tripartite motif containing 39 56658 Q9HCM9 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
TRIP13 thyroid hormone receptor interactor 13 9319 Q15645 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
UBC ubiquitin C 7316 P63279 LC-MS/MS
Danielsen JM , et al. 2010
ZBTB43 zinc finger and BTB domain containing 43 23099 O43298 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
FMR1 fragile X mental retardation 1 14265 P35922 HITS-CLIP
Darnell JC , et al. 2011

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