Alternative titles; symbols
HGNC Approved Gene Symbol: PRICKLE2
Cytogenetic location: 3p14.1 Genomic coordinates (GRCh38) : 3:64,092,236-64,268,173 (from NCBI)
The PRICKLE2 gene encodes a postsynaptic protein involved in neuronal architecture and function (summary by Sowers et al., 2013).
By searching an EST database for sequences similar to those of Drosophila and Xenopus Prickle, Katoh and Katoh (2003) identified human PRICKLE2. The deduced 844-amino acid protein contains an N-terminal PET domain followed by 3 LIM domains and a C-terminal prickle homology domain. PRICKLE2 shares 51.9% overall identity with PRICKLE1 (608500) and 79.3% identity within the N-terminal PET and LIM domains. EST database analysis revealed that PRICKLE1 and PRICKLE2 are coexpressed in brain, eye, and testis; additionally, PRICKLE2 is expressed in fetal brain, adult cartilage, pancreatic islet, gastric cancer, and uterine tumor.
Tao et al. (2011) found expression of Prickle2 in the hippocampus and cerebral cortex of mice.
Katoh and Katoh (2003) determined that the PRICKLE2 gene contains at least 8 exons and that the 5-prime untranslated region is interrupted by intron 1.
By genomic sequence analysis, Katoh and Katoh (2003) mapped the PRICKLE2 gene to chromosome 3p14, and the mouse Prickle2 gene to chromosome 6.
Associations Pending Confirmation
For discussion of a possible association between variation in the PRICKLE2 gene and myoclonic epilepsy, see 608501.0001 and 608501.0002.
In 2 pairs of sibs from 2 unrelated families with autism (209850), Sowers et al. (2013) identified 2 different heterozygous missense variants in the PRICKLE2 gene (glu8-to-gln (E8Q) and val143-to-ile (V153I), respectively). In both families, the variant was inherited from a father with expressive language delay (family A) and several psychiatric features, including depression, anxiety, obsessive-compulsive disorder, and learning difficulties (family B). Neither variant was present in the 1000 Genomes Project or in 192 controls: the E8Q variant was not found in the Exome Sequencing Project database, whereas V143I was present at a low frequency (0.001%) in that database. Of note, E8Q is highly conserved, but an isoleucine at residue 143 is present in the mouse sequence, but not in several other animals. The patients were ascertained from a cohort of 384 patients with autism spectrum disorder who underwent sequencing of the PRICKLE2 gene. In vitro functional expression studies showed that neither variant was able to rescue morphologic and functional abnormalities of Prickle2-null mouse neurons, suggesting that the mutations caused a partial loss of function. Sowers et al. (2013) concluded that variation in the PRICKL2 gene may contribute to autism spectrum disorders.
Tao et al. (2011) identified a heterozygous deletion of the PRICKLE2 gene (62,665,527-64,890,116) in a male patient with developmental delay, epilepsy, and autistic disorder.
Tao et al. (2011) found that heterozygous Prickle +/- mice had a decreased seizure threshold compared to wildtype mice. Prickle2-null mice were viable, but showed an increased seizure rate compared to heterozygous mice, indicating a dosage effect.
Sowers et al. (2013) stated that Prickle2 is highly expressed in the mouse hippocampus and localizes to the postsynaptic region. Prickle2-null mice showed increased hippocampal-dependent learning in contextual fear conditioning studies compared to wildtype, although they demonstrated decreased behavioral flexibility and reduced sociability. Postmortem studies showed that mutant mice had decreased size of the postsynaptic region and decreased synapse number compared to wildtype, and these changes were associated with a decrease in frequency of miniature excitatory and inhibitory postsynaptic currents in hippocampal slices and primary neurons. Prickle2-null neurons also showed a decrease in dendritic arborization, which could be rescued by expression of the wildtype gene.
Mei et al. (2014) found that pk2 knockdown led to body curvature and inner plexiform layer neurogenesis defects in zebrafish. Pk2 knockdown disrupted morphogenesis of Kupffer vesicles (KVs) in zebrafish, similar to findings in bbs7 (607590) knockdown zebrafish, suggesting that pk2 and bbs7 might functionally interact. However, KV morphology defects in pk2 and bbs7 double-knockdown zebrafish appeared to be additive rather than synergistic. Further analysis of cilia length, neural tube polarity, protein localization, protein interaction, and intracellular transport confirmed that pk2 and bbs7 did not act synergistically. The authors proposed that pk2 and bbs7 act independently in distinct pathways that, in specific tissue contexts, converge on the same processes.
This variant, formerly titled EPILEPSY, PROGRESSIVE MYOCLONIC, 5 based on the findings of Tao et al. (2011), has been reclassified based on the findings of Sandford et al. (2016).
In a sister and brother with severe progressive myoclonic epilepsy, originally reported by Bird and Shaw (1978), Tao et al. (2011) identified heterozygosity for a complex mutation in the PRICKLE2 gene: a 443G-A transition, resulting in an arg148-to-his (R148H) substitution, and a 457G-A transition, resulting in a val153-to-ile (V153I) substitution. Studies of the orthologous double variation in zebrafish embryos showed that it resulted in increased prickle2 activity compared to wildtype, as measured by convergent-extension movements during gastrulation. In addition, the R148H/V153I-variant protein was less active in stimulating calcium release compared to wildtype.
By reevaluation of the sibs reported by Tao et al. (2011), Sandford et al. (2016) determined that the 2 heterozygous missense variants in the PRICKLE2 gene identified by Tao et al. (2011) occurred on opposite chromosomes, which would be more consistent with recessive inheritance. Furthermore, in these sibs, Sandford et al. (2016) identified compound heterozygous mutations in the POLG gene (A467T, 174763.0002 on 1 allele, and W748S, 174763.0013 and G497H, 174763.0016 in cis on the other allele). Sandford et al. (2016) concluded that the phenotype (see 607459) resulted from the POLG mutations and not from the PRICKLE2 variants. In a response, Mahajan and Bassuk (2016) maintained that the PRICKLE2 variants identified by Tao et al. (2011) contributed to the phenotype in their patients.
This variant, formerly titled EPILEPSY, PROGRESSIVE MYOCLONIC, 5 based on the findings of Tao et al. (2011), has been reclassified based on the findings of Sandford et al. (2016).
In a male patient with myoclonic seizures, Tao et al. (2011) identified a heterozygous 1813G-T transversion in the PRICKLE2 gene, resulting in a val605-to-phe (V605F) substitution. Studies of the orthologous V605F variant in zebrafish embryos showed that it resulted in decreased prickle2 activity compared to wildtype, as measured by convergent-extension movements during gastrulation. In addition, the V605F-variant protein was less active in stimulating calcium release compared to wildtype.
Sandford et al. (2016) stated that the PRICKLE2 V605F variant identified in a patient by Tao et al. (2011) appears twice in the ExAC database, and thus is not consistent with its being pathogenic. In a response, Mahajan and Bassuk (2016) maintained that the PRICKLE2 variant identified by Tao et al. (2011) contributed to the phenotype in the patient.
Bird, T. D., Shaw, C. M. Progressive myoclonus and epilepsy with dentatorubral degeneration: a clinicopathological study of the Ramsay Hunt syndrome. J. Neurol. Neurosurg. Psychiat. 41: 140-149, 1978. [PubMed: 632821] [Full Text: https://doi.org/10.1136/jnnp.41.2.140]
Katoh, M., Katoh, M. Identification and characterization of human PRICKLE1 and PRICKLE2 genes as well as mouse Prickle1 and Prickle2 genes homologous to Drosophila tissue polarity gene prickle. Int. J. Molec. Med. 11: 249-256, 2003. [PubMed: 12525887]
Mahajan, V. B., Bassuk, A. G. Response to Sandford et al.: PRICKLE2 variants in epilepsy: a call for precision medicine Am. J. Hum. Genet. 98: 590-591, 2016. [PubMed: 26942292] [Full Text: https://doi.org/10.1016/j.ajhg.2016.02.002]
Mei, X., Westfall, T. A., Zhang, Q., Sheffield, V. C., Bassuk, A. G., Slusarski, D. C. Functional characterization of Prickle2 and BBS7 identify overlapping phenotypes yet distinct mechanisms. Dev. Biol. 392: 245-255, 2014. [PubMed: 24938409] [Full Text: https://doi.org/10.1016/j.ydbio.2014.05.020]
Sandford, E., Bird, T. D., Li, J. Z., Burmeister, M. PRICKLE2 mutations might not be involved in epilepsy. (Letter) Am. J. Hum. Genet. 98: 588-589, 2016. [PubMed: 26942291] [Full Text: https://doi.org/10.1016/j.ajhg.2016.01.009]
Sowers, L. P., Loo, L., Wu, Y., Campbell, E., Ulrich, J. D., Wu, S., Paemka, L., Wassink, T., Meyer, K., Bing, X., El-Shanti, H., Usachev, Y. M., and 9 others. Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction. Molec. Psychiat. 18: 1077-1089, 2013. Note: Erratum: Molec. Psychiat. 19: 742 only, 2014. [PubMed: 23711981] [Full Text: https://doi.org/10.1038/mp.2013.71]
Tao, H., Manak, J. R., Sowers, L., Mei, X., Kiyonari, H., Abe, T., Dahdaleh, N. S., Yang, T., Wu, S., Chen, S., Fox, M. H., Gurnett, C., and 24 others. Mutations in prickle orthologs cause seizures in flies, mice, and humans. Am. J. Hum. Genet. 88: 138-149, 2011. [PubMed: 21276947] [Full Text: https://doi.org/10.1016/j.ajhg.2010.12.012]