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Relevance to Autism

Rare variants in the RAPGEF4 gene have been identified with autism; however, the same study found no genetic association between the RAPGEF4 gene and autism in an IMGSAC cohort (Bacchelli et al., 2003).

Molecular Function

The encoded protein acts as a cAMP sensor and mediates cAMP-dependent, protein k inase A-independent exocytosis.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene.
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
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
ASD
Support
Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.
ASD
Highly Cited
A family of cAMP-binding proteins that directly activate Rap1.
Recent Recommendation
Neuronal AKAP150 coordinates PKA and Epac-mediated PKB/Akt phosphorylation.
Recent Recommendation
An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.
Recent Recommendation
Depolarization and Ca(2) down regulate CB1 receptors and CB1-mediated signaling in cerebellar granule neurons.
Recent Recommendation
EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation.
Recent Recommendation
Valproate-induced alterations in human theca cell gene expression: clues to the association between valproate use and metabolic side effects.
Recent Recommendation
Mechanism of intracellular cAMP sensor Epac2 activation: cAMP-induced conformational changes identified by amide hydrogen/deuterium exchange mass s...
Recent Recommendation
Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines.
Recent Recommendation
Ras is required for the cyclic AMP-dependent activation of Rap1 via Epac2.
Recent Recommendation
Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B.
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN209R001 
 missense_variant 
 c.494T>C 
 p.Met165Thr 
 Familial 
 Paternal 
 Multiplex 
 GEN209R002 
 missense_variant 
 c.1936G>T 
 p.Val646Phe 
 Familial 
 Maternal 
 Multiplex 
 GEN209R003 
 missense_variant 
 c.2116G>A 
 p.Gly706Arg 
 Familial 
 Paternal 
 Multiplex 
 GEN209R004 
 missense_variant 
 c.2426C>G 
 p.Thr809Ser 
 Familial 
 Paternal 
 Multiplex 
 GEN209R005 
 splice_site_variant 
 c.2268+1G>A 
  
 De novo 
  
  
 GEN209R006 
 missense_variant 
 c.2210A>G 
 p.Asn737Ser 
 De novo 
  
 Simplex 
 GEN209R007 
 synonymous_variant 
 c.105C>T 
 p.Asn35= 
 De novo 
  
 Simplex 
 GEN209R008 
 splice_site_variant 
 c.105+1G>A 
  
 Unknown 
  
 Simplex 
 GEN209R009 
 missense_variant 
 c.554G>A 
 p.Arg185Lys 
 De novo 
  
 Multiplex 
 GEN209R010 
 splice_site_variant 
 c.85+1G>C 
  
 Familial 
 Paternal 
 Multiplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
2
Duplication
 1
 
2
Deletion
 3
 
2
Deletion
 1
 
2
Deletion-Duplication
 16
 
2
Deletion
 3
 
2
Deletion
 1
 

Model Summary

Epac2/Rap1 signaling is essential in regulation of insulin granule dynamics by cAMP, most likely by controlling granule density near the plasma membrane.

References

Type
Title
Author, Year
Primary
Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP.
Additional
Perseverative stereotypic behavior of Epac2 KO mice in a reward-based decision making task

M_RAPGEF4_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: loxP/Cre mediated excision of 1.3-kb DNA fragment containing part of exon 1 and intron 1 of the mouse Epac2 gene.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not Specified
Genetic Background: Not Specified
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_RAPGEF4_2_KO_HM

Model Type: Genetic LOF
Model Genotype: Homozygous
Mutation: Rapgef4 mutant mice lacking the rapgef4 gene were generated using the cre-loxp targeting to delete exon3 and ablate expression of rapegef4.
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_RAPGEF4_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Hormone levels1
Decreased
Description: Decreased potentiation of first phase of glucose induced fusion by 8-bromo-camp
Exp Paradigm: Tirfm analysis of isolated pancreatic beta cells
 Total internal reflection fluorescence microscopy (tirfm)
 7 weeks
Enzyme activity1
Decreased
Description: Absence of rap1 protein activation by 8-bromo-camp
Exp Paradigm: Rap1 protein activation
 Immunohistochemistry
 7 weeks
Hormone levels1
 No change
 Total internal reflection fluorescence microscopy (tirfm)
 7 weeks
 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_RAPGEF4_2_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuronal number: Interneurons1
Decreased
Description: Decreased pv positive gabaergic interneurons or fast spiking interneurons in the orbitofrontal cortex but not dorsal striatum; no change in chat positive interneurons; no change in density of msns and cholinergic interneurons
 Immunohistochemistry
 12 weeks
Network excitability1
Decreased
Description: Lack of increased striatal fsi excitability following dopamine treatment
 Whole-cell patch clamp
 12 weeks
Stereotypy1
Increased
Description: Increase in consecutive same choices;
 Operant conditioning paradigm
 12 weeks
Bioactive compound levels1
Decreased
Description: Decreased intracellular concentration of camp in the dstr but not hip, indicating reduced camp-mediated response to d1-like receptor activation resulting in reduced activity of pv-positive fsi
 Enzyme assay
 12 weeks
Reward reinforced choice behavior1
Decreased
Description: Decreased learning rate; preservative behavior of the ko mice was independent of reward probability; increase in beta rate indicating low randomness of choice
 Operant conditioning paradigm
 12 weeks
Cognitive flexibility: Associative learning1
Decreased
Description: Decreased switch rate of choosing the same goal or different goal over consecutive trials, increase in selecting the same goal in a series of consecutive trials
 Operant conditioning paradigm
 12 weeks
Targeted expression1
Decreased
Description: Lack of rapgef4 transcript
 RNA sequencing
 12 weeks
Cued or contextual fear conditioning: Active avoidance1
 No change
 T-maze test
 12 weeks
Neuronal number1
 No change
 Immunohistochemistry
 12 weeks
Action potential property: firing rate1
 No change
 Whole-cell patch clamp
 12 weeks
Action potential property: rate of depolarization1
 No change
 Whole-cell patch clamp
 12 weeks
Action potential property: threshold1
 No change
 Whole-cell patch clamp
 12 weeks
Intrinsic membrane properties1
 No change
 Whole-cell patch clamp
 12 weeks
Membrane potential1
 No change
 Whole-cell patch clamp
 12 weeks
 Not Reported:





Download RAPGEF4's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
ATXN1 ataxin 1 6310 P54253 Y2H
Lim J , et al. 2006
BZRAP1 benzodiazapine receptor (peripheral) associated protein 1 9256 O95153 Y2H
Corominas R , et al. 2014
C16ORF45 chromosome 16 open reading frame 45 NM_033201 Q96MC5 Y2H
Corominas R , et al. 2014
C16ORF45 chromosome 16 open reading frame 45 NM_033201 Q96MC5 Y2H; bimolecular fluorescence complementation assay
Rolland T , et al. 2014
MAP1A microtubule-associated protein 1A 4130 P78559 IP/WB
Magiera MM , et al. 2004
RAP1A RAP1A, member of RAS oncogene family 5906 P62834 GTP hydrolysis assay
de Rooij J , et al. 2000
RAP2A RAP2A, member of RAS oncogene family 5911 P10114 GTP hydrolysis assay
de Rooij J , et al. 2000
SWAP70 SWAP switching B-cell complex 70kDa subunit 23075 Q9UH65 Y2H
Corominas R , et al. 2014
TRAF2 TNF receptor-associated factor 2 7186 Q12933 Y2H
Corominas R , et al. 2014
ZC3H11A zinc finger CCCH-type containing 11A 9877 O75152 Y2H
Corominas R , et al. 2014
Abcc8 ATP-binding cassette, subfamily C (CFTR/MRP), member 8 25559 Q09429 Y2H; Affinity chromatography
Shibasaki T , et al. 2003
FMR1 fragile X mental retardation 1 14265 P35922 HITS-CLIP
Darnell JC , et al. 2011
RAP1B RAP1B, member of RAS oncogene family 5908 P61224 X-ray crystallography; Single particle electron microscopy
Rehmann H , et al. 2008
Rims2 regulating synaptic membrane exocytosis 2 116838 Q9EQZ7 Y2H; GST; IP/WB
Ozaki N , et al. 2000
Nlgn1 neuroligin 1 116647 Q62765 IP/WB
Woolfrey KM , et al. 2009
Nlgn2 neuroligin 2 117096 Q62888 IP/WB
Woolfrey KM , et al. 2009
Nlgn3 neuroligin 3 171297 Q62889 IP/WB
Woolfrey KM , et al. 2009

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