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Relevance to Autism

Mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number and PSD size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. Distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) were identified in two ASD cases that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays (Sowers et al., 2013).

Molecular Function

This gene encodes a homolog of Drosophila prickle. The exact function of this gene is not known, however, studies in mice suggest that it may be involved in seizure prevention. Mutations in this gene are associated with progressive myoclonic epilepsy type 5.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.
ASD
Support
Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes.
ASD
Support
Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.
ASD
Support
Mutations in prickle orthologs cause seizures in flies, mice, and humans.
Epilepsy
ASD, DD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN545R001 
 missense_variant 
 c.22G>C 
 p.Glu8Gln 
 Familial 
 Paternal 
 Multi-generational 
 GEN545R002 
 missense_variant 
 c.457G>A 
 p.Val153Ile 
 Familial 
 Paternal 
 Multi-generational 
 GEN545R003 
 missense_variant 
 c.443G>A 
 p.Arg148His 
 Unknown 
  
 Multiplex 
 GEN545R004 
 missense_variant 
 c.457G>A 
 p.Val153Ile 
 Unknown 
  
 Multiplex 
 GEN545R005 
 missense_variant 
 c.1813G>T 
 p.Val605Phe 
 Unknown 
  
 Unknown 
 GEN545R006 
 copy_number_loss 
  
  
 Unknown 
  
 Unknown 
 GEN545R007 
 missense_variant 
 c.2419G>T 
 p.Asp807Tyr 
 Familial 
 Paternal 
 Multiplex 
 GEN545R008 
 missense_variant 
 c.1891A>G 
 p.Arg631Gly 
 De novo 
 NA 
  

Common

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

Model Summary

Prickle mutations have caused seizures throughout evolution.

References

Type
Title
Author, Year
Primary
Mutations in prickle orthologs cause seizures in flies, mice, and humans.
Additional
Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.

M_PRICKLE2_1_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Gene targeting of Prickle2 in TT2 ES Cells.
Allele Type: Targeted (Deletion)
Strain of Origin:
Genetic Background: C57BL/6
ES Cell Line: TT2
Mutant ES Cell Line:
Model Source:

M_PRICKLE2_2_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Gene targeting of Prickle2 in TT2 ES Cells.
Allele Type: Targeted (Deletion)
Strain of Origin:
Genetic Background: C57BL/6
ES Cell Line: TT2
Mutant ES Cell Line:
Model Source:

M_PRICKLE2_1_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Seizure threshold1
Decreased
Description: Decreased Seizure threshold indicated by increased Seizure predisposition
Exp Paradigm: Maximal electroconvulsive Seizure threshold (MEST)
 Maximal electroconvulsive seizure threshold test
 Unreported
Social interaction2
Decreased
Description: Decreased social interaction indicated by less time interacting with novel mouse
Exp Paradigm: Freely moving social assay
 Resident-intruder test
 8-12 weeks
Cued or contextual fear conditioning: memory of context2
Increased
Description: Abnormal contextual fear conditioning indicated by increased freezing during acquisition and recall
Exp Paradigm: Hippocampus-dependent contextual fear conditioning
 Fear conditioning test
 8-12 weeks
Cognitive flexibility2
Decreased
Description: Decreased reversal learning indicated by delayed acquisition of target hole
Exp Paradigm: Reversal learning in Barnes maze test
 Barnes maze test
 8-12 weeks
Response to novelty2
 No change
 Novel object recognition test
 8-12 weeks
Cued or contextual fear conditioning: memory of cue2
 No change
 Fear conditioning test
 8-12 weeks
Spatial learning2
 No change
 Barnes maze test
 8-12 weeks
General locomotor activity2
 No change
 Open field test
 8-12 weeks
Olfaction2
 No change
 Predator odor (tmt) test
 8-12 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_PRICKLE2_2_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Post-synaptic density size2
Decreased
Description: Decreased PSD size and synapse number in both DG and CA1 of hippocampus
Exp Paradigm: Transmission electron microscopy of hippocampus
 Electron microscopy
 8-12 weeks
Synaptic transmission2
Decreased
Description: Decreased synaptic transmission indicated by reduced frequency of both mEPSCs and mIPSCs with No Change in amplitude
Exp Paradigm: Whole-cell patch-clamp recordings of miniature excitatory post-synaptic currents from hippocampal slices
 Whole-cell patch clamp
 8-12 weeks
Seizures1
Increased
Description: Increased Seizure rates and epileptiform discharges after treatment with Seizure-inducing GABA agonist pentylenetetrazole (PTZ)
Exp Paradigm: PTZ evoked Seizures and electrocorticography recordings
 Observation of chemically induced seizures
 Unreported
Social interaction2
Decreased
Description: Decreased social interaction indicated by less time interacting with novel mouse
Exp Paradigm: Freely moving social assay
 Resident-intruder test
 8-12 weeks
Social interaction2
Decreased
Description: Decreased social interaction indicated by less time spent directly interaction with unfamiliar mouse
Exp Paradigm: Three chamber social assay
 Three-chamber social approach test
 8-12 weeks
Spatial learning2
Decreased
Description: Decreased spatial learning indicated by more time spent in target quadrant
Exp Paradigm: Barnes maze test
 Barnes maze test
 8-12 weeks
Cued or contextual fear conditioning: memory of context2
Increased
Description: Abnormal contextual fear conditioning indicated by increased freezing during acquisition and recall
Exp Paradigm: Hippocampus-dependent contextual fear conditioning
 Fear conditioning test
 8-12 weeks
Cognitive flexibility2
Decreased
Description: Decreased reversal learning indicated by delayed acquisition of target hole
Exp Paradigm: Reversal learning in Barnes maze test
 Barnes maze test
 8-12 weeks
Protein expression level evidence1
Decreased
Description: Decreased expression of Prickle2 in epilepsy-associated brain regions, hippocampus, cerebral cortex
Exp Paradigm: Prickle2 Expression
 Immunohistochemistry
 Unreported
Mortality/lethality1
 No change
 General observations
 Unreported
Response to novelty2
 No change
 Novel object recognition test
 8-12 weeks
Cued or contextual fear conditioning: memory of cue2
 No change
 Fear conditioning test
 8-12 weeks
General locomotor activity2
 No change
 Open field test
 8-12 weeks
Post-synaptic density size2
 No change
 Electron microscopy
 8-12 weeks
Olfaction2
 No change
 Predator odor (tmt) test
 8-12 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / ultrastructure / cytoarchitecture, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
APP amyloid beta (A4) precursor protein 351 P05067 Protein microarray
Olh J , et al. 2011
Bcr breakpoint cluster region 309696 IP; LC-MS/MS; IP/WB
Paemka L , et al. 2015
Cad carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase 24240 IP; LC-MS/MS
Paemka L , et al. 2015
DVL1 dishevelled, dsh homolog 1 (Drosophila) 1855 O14640 IP/WB
Narimatsu M , et al. 2009
Mycbp2 MYC binding protein 2, E3 ubiquitin protein ligase 290447 IP; LC-MS/MS
Paemka L , et al. 2015
PAR6 par-6 family cell polarity regulator alpha 50855 Q9NPB6 IP/WB
Narimatsu M , et al. 2009
Rpl23 ribosomal protein L23 29282 P62832 IP; LC-MS/MS
Paemka L , et al. 2015
Rpl4 ribosomal protein L4 64302 P50878 IP; LC-MS/MS
Paemka L , et al. 2015
Rps26 ribosomal protein S26 27139 P62856 IP; LC-MS/MS
Paemka L , et al. 2015
Smurf2 SMAD specific E3 ubiquitin protein ligase 2 64750 Q96DE7 IP/WB
Narimatsu M , et al. 2009
Tanc1 tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 1 311055 Q6F6B3 IP; LC-MS/MS
Paemka L , et al. 2015
Tanc2 tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2 303599 F1LTE0 IP; LC-MS/MS; IP/WB
Paemka L , et al. 2015
Tubb4b ubulin, beta 4B class IVb 296554 Q6P9T8 IP; LC-MS/MS
Paemka L , et al. 2015
Tubb5 tubulin, beta 5 class I 29214 P69897 IP; LC-MS/MS
Paemka L , et al. 2015
UBC ubiquitin C 7316 P63279 LC-MS/MS
Danielsen JM , et al. 2010
Usp9x ubiquitin specific peptidase 9, X-linked 363445 D3ZC84 IP; LC-MS/MS; IP/WB
Paemka L , et al. 2015
FMR1 fragile X mental retardation 1 14265 P35922 HITS-CLIP
Darnell JC , et al. 2011

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