Human Gene Module / Chromosome 3 / PRICKLE2

PRICKLE2prickle planar cell polarity protein 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
14 / 0
Aliases
PRICKLE2, EPM5
Associated Syndromes
-
Chromosome Band
3p14.1
Associated Disorders
DD/NDD, ASD, EPS
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.

SFARI Genomic Platforms
Reports related to PRICKLE2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Mutations in prickle orthologs cause seizures in flies, mice, and humans Tao H , et al. (2011) No ASD, DD
2 Primary Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction Sowers LP , et al. (2013) Yes -
3 Support Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations Toma C , et al. (2013) Yes -
4 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Support - Bayat A et al. (2021) No ASD or autistic features, epilepsy/seizures
6 Support - Zhou X et al. (2022) Yes -
7 Support - Dorrego-Rivas A et al. (2022) No -
8 Support - et al. () Yes -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - Unknown 21276947 Tao H , et al. (2011)
c.972C>T p.Ser324%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.214C>T p.Arg72Ter stop_gained De novo - Simplex 34092786 Bayat A et al. (2021)
c.1891A>G p.Arg631Gly missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.122C>T p.Pro41Leu missense_variant De novo - Simplex 34092786 Bayat A et al. (2021)
c.1813G>T p.Val605Phe missense_variant Unknown - Unknown 21276947 Tao H , et al. (2011)
c.680C>G p.Thr227Arg missense_variant De novo - Simplex 34092786 Bayat A et al. (2021)
c.443G>A p.Arg148His missense_variant Unknown - Multiplex 21276947 Tao H , et al. (2011)
c.457G>A p.Val153Ile missense_variant Unknown - Multiplex 21276947 Tao H , et al. (2011)
c.1806A>G p.Ala602%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.22G>C p.Glu8Gln missense_variant Familial Paternal Multiplex 23711981 Sowers LP , et al. (2013)
c.2419G>T p.Asp807Tyr missense_variant Familial Paternal Multiplex 23999528 Toma C , et al. (2013)
c.457G>A p.Val153Ile missense_variant Familial Paternal Multiplex 23711981 Sowers LP , et al. (2013)
c.1286_1287del p.Ser429ThrfsTer56 frameshift_variant Familial Maternal Multi-generational 34092786 Bayat A et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons lead 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). Defects in PRICKLE2 are the cause of progressive myoclonic epilepsy type 5 (EPM5)[MIM:613832], a neurodegenerative disorder characterized by myoclonic seizures and variable neurologic symptoms including cognitive decline and persistent movement abnormalities.

Score Delta: Score remained at 2

2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2021
2
icon
2

Score remained at 2

Description

Mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons lead 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). Defects in PRICKLE2 are the cause of progressive myoclonic epilepsy type 5 (EPM5)[MIM:613832], a neurodegenerative disorder characterized by myoclonic seizures and variable neurologic symptoms including cognitive decline and persistent movement abnormalities.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons lead 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). Defects in PRICKLE2 are the cause of progressive myoclonic epilepsy type 5 (EPM5)[MIM:613832], a neurodegenerative disorder characterized by myoclonic seizures and variable neurologic symptoms including cognitive decline and persistent movement abnormalities.

7/1/2015
icon
3

Increased from to 3

Description

Mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons lead 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). Defects in PRICKLE2 are the cause of progressive myoclonic epilepsy type 5 (EPM5) [MIM:613832], a neurodegenerative disorder characterized by myoclonic seizures and variable neurologic symptoms including cognitive decline and persistent movement abnormalities.

Krishnan Probability Score

Score 0.49428874399904

Ranking 3740/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.98783718573076

Ranking 1894/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.94133597971328

Ranking 14895/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 21

Ranking 101/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.33446820033563

Ranking 2217/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
PAR6 par-6 family cell polarity regulator alpha Human Protein Binding 50855 Q9NPB6
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