Mutations in Prickle Orthologs Cause Seizures in Flies, Mice, and Humans

Tao, Hirotaka; Manak, J. Robert; Sowers, Levi P.; Xue, Mei; Kanazawa, Hiroshi; Abe, Takaya; Dahdaleh, Nader S.; Yang, Tian; Wu, Shu; Chen, Shan; Fox, Michael; Gurnett, Christina A.; Montine, Thomas J.; Bird, Thomas D.; Shaffer, Lisa G.; Rosenfeld, Jill A.; McConnell, Juliann; Madan‐Khetarpal, Suneeta; Berry‐Kravis, Elizabeth; Griesbach, Hilary; Saneto, Russell P.; Scott, Matthew P.; Antic, Dragana; Reed, Jordan; Boland, Riley; Ehaideb, Salleh N.; El‐Shanti, Hatem; Mahajan, Vinit B.; Ferguson, Polly J.; Axelrod, Jeffrey; Lehesjoki, Anna Elina; Fritzsch, Bernd; Slusarski, Diane C.; Wemmie, John A.; Ueno, Naoto; Bassuk, Alexander G.

doi:10.1016/j.ajhg.2010.12.012

Cited by 133 publications

(249 citation statements)

References 54 publications

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“…We recently reported that Prickle2 deficient mice have a lower seizure threshold and PRICKLE2 mutations in humans are associated with epilepsy (18). In that report, one individual with a PRICKLE2-encompassing deletion had both epilepsy and ASD.…”

Section: Introductionmentioning

confidence: 99%

“…Prickle2 is a highly expressed in the mouse hippocampus (a region associated with seizure susceptibility), localizes to the PSD, and its disruption is associated with epilepsy in humans and decreased seizure threshold in mice (18,21,31). It is well established that abnormalities in the hippocampus can underlie seizure susceptibility (31).…”

Section: Behavioral Abnormalities In Prickle2 Disrupted Micementioning

confidence: 99%

“…Prickle2 is highly expressed in the hippocampal formation, a brain region associated with epilepsy pathogenesis (9,31,32). Moreover, Prickle2 localizes to the post-synaptic density (PSD) (16,18) and interacts with PSD-95 and the NMDA receptor, two proteins implicated in ASDs (16,33).…”

Section: Introductionmentioning

confidence: 99%

“…Canonical Wnt signaling is mediated through itnracellular β-catenin whereas, the non-canonical Wnt pathway is β-catenin-independent and signals through core planar cell polarity (PCP) proteins including Prickle (19,20). Transgenic mice with manipulations in Wnt genes display a variety of behavioral abnormalities including seizures, abnormal learning, and repetitive behaviors (18,(21)(22)(23). Accordingly, ASD-like phenotypes in mice were linked to mutations in genes of the Wnt/PCP pathway (21,22).…”

Section: Introductionmentioning

confidence: 99%

“…The Wnt signaling pathway regulates a myriad of neurodevelopmental processes, e.g., cell fate determination, axon migration, dendritic arborization, and synapse formation (10)(11)(12)(13)(14)(15)(16)(17)(18). There are two major pathways that define the Wnt signaling pathway; the canonical and non-canonical pathways.…”

Section: Introductionmentioning

confidence: 99%

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Erratum: Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction

Sowers¹,

Loo²,

Wu³

et al. 2013

Mol Psychiatry

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Author Contributions: LPS contributed to all experiments, planning, and writing of the paper. LL performed all in vitro electrophysiology. YW performed in vivo electrophysiology. LL, LPS and DPM analyzed all the electrophysiology data. EC performed mouse behavioral experiments. YMU and JU performed a part of primary hippocampal neuron cultures. SW performed western blot experiments. JRM, HEL, LP, TW, XY and KM aided in the collection and sequencing of human DNA. PF, NU and SW conducted production and breeding of mice of different genotypes used in this study. AJS assisted in all immunocytochemistry experiments and analysis. GBR, DPM, and JM provided reagents, supervised experiments and analysis, and aided in manuscript writing. JAW provided all behavioral equipment. JAW and DPM provided scientific input to the study design. BWD provided statistical analysis for whole exome sequencing data. All authors contributed to the writing of this manuscript. AGB supervised all aspects of the project design, execution and writing of the paper. The datasets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000298.v1.p1, under dbGAP Research Project #4357 (Variation in PRICKLE2 and related Genes in Autism) to AGB. The data set(s) were deposited by the ARRA Autism Sequencing Collaborative, an ARRA funded research initiative. AbstractAutism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post synaptic density 95 (PSD-95). Here we show that 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 post-synaptic density 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. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) 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. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribu...

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Section: Introductionmentioning

confidence: 99%

Section: Behavioral Abnormalities In Prickle2 Disrupted Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Erratum: Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction

Sowers¹,

Loo²,

Wu³

et al. 2013

Mol Psychiatry

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Mutation of orthologous prickle genes causes a similar epilepsy syndrome in flies and humans

Ehaideb

Wignall

Kasuya

et al. 2016

Ann Clin Transl Neurol

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ObjectiveGenetically tractable fruit flies have been used for decades to study seizure disorders. However, there is a paucity of data specifically correlating fly and human seizure phenotypes. We have previously shown that mutation of orthologous PRICKLE genes from flies to humans produce seizures. This study aimed to determine whether the prickle‐mediated seizure phenotypes in flies closely parallel the epilepsy syndrome found in PRICKLE patients.MethodsVirtually all fly seizure studies have relied upon characterizing seizures that are evoked. We have developed two novel approaches to more precisely characterize seizure‐related phenotypes in their native state in prickle mutant flies. First, we used high‐resolution videography to document spontaneous, unprovoked seizure events. Second, we developed a locomotion coordination assay to assess whether the prickle mutant flies were ataxic. Third, we treated the mutant flies with levetiracetam to determine whether the behavioral phenotypes could be suppressed by a common antiepileptic drug.ResultsWe find that the prickle mutant flies exhibit myoclonic‐like spontaneous seizure events and are severely ataxic. Both these phenotypes are found in human patients with PRICKLE mutations, and can be suppressed by levetiracetam, providing evidence that the phenotypes are due to neurological dysfunction. These results document for the first time spontaneous, unprovoked seizure events at high resolution in a fly human seizure disorder model, capturing seizures in their native state.InterpretationCollectively, these data underscore the striking similarities between the fly and human PRICKLE‐mediated epilepsy syndromes, and provide a genetically tractable model for dissecting the underlying causes of the human syndromic phenotypes.

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3p14 deletion is a rare contiguous gene syndrome: Report of 2 new patients and an overview of 14 patients

Dimitrov

Ogilvie

Wieczorek

et al. 2015

American J of Med Genetics Pt A

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Interstitial deletions of chromosome 3p14p12 are a rare chromosome rearrangement. Twenty-six patients have been reported in the literature to date, however, a specific clinical phenotype has not yet been delineated. We describe three patients (two new) with overlapping chromosome 3p14p12 deletions and review the clinical and molecular data of 11 well-characterized, published cases. These patients had a number of features in common, such as short stature, failure to thrive, facial dysmorphism, congenital heart defects, urogenital abnormalities, neurological problems, hearing loss, and global developmental delay, suggesting that the interstitial chromosome 3p14p12 deletion gives rise to a multiple congenital anomaly syndrome. Some of the patients show clinical overlap with other complex syndromes such as CHARGE syndrome. Genotype-phenotype analysis revealed candidate genes for parts of the clinical features suggesting that the 3p14 deletion is a contiguous gene syndrome.

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Mutations in Prickle Orthologs Cause Seizures in Flies, Mice, and Humans

Cited by 133 publications

References 54 publications

Erratum: Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction

Erratum: Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction

Mutation of orthologous prickle genes causes a similar epilepsy syndrome in flies and humans

3p14 deletion is a rare contiguous gene syndrome: Report of 2 new patients and an overview of 14 patients

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