Alternative titles; symbols
HGNC Approved Gene Symbol: PRICKLE1
SNOMEDCT: 702326000;
Cytogenetic location: 12q12 Genomic coordinates (GRCh38) : 12:42,456,757-42,589,746 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q12 | Epilepsy, progressive myoclonic 1B | 612437 | Autosomal recessive | 3 |
PRICKLE proteins, such as PRICKLE1, are core constituents of the planar cell polarity signaling pathway that establishes cell polarity during embryonic development (Liu et al., 2013).
Using mouse Rest4 (see REST, 600571) as bait in a yeast 2-hybrid screen, Shimojo and Hersh (2003) cloned rat Prickle1, which they designated Rilp, from a rat brain cDNA library. By screening a human brain cDNA library with rat Rilp cDNA fragments, followed by 5-prime and 3-prime RACE, they obtained full-length human PRICKLE1. The deduced 831-amino acid protein contains 3 N-terminal LIM domains and 3 C-terminal nuclear localization signals. It also contains 4 N-glycosylation sites, 2 PKA (see 176911) phosphorylation sites, and a C-terminal CIIS (cys-ile-ile-ser) prenylation motif. Northern blot analysis detected a single 4.4-kb transcript in all tissues examined, with the highest level in placenta. Western blot analysis detected in vitro translated PRICKLE1 at an apparent molecular mass of 100 kD. SDS-PAGE and Western blot analysis of HeLa cell extracts showed endogenous PRICKLE1 in the nuclear fraction, with a smaller amount in the cytosolic extract. Immunolocalization showed endogenous PRICKLE1 localized around HeLa cell nuclei, and proteinase digestion indicated that at least a portion of PRICKLE1 is localized to the outer nuclear membrane.
By searching an EST database for sequences similar to those of Drosophila and Xenopus Prickle, Katoh and Katoh (2003) identified human PRICKLE1. The deduced protein contains a PET domain N-terminal to the 3 LIM domains. PRICKLE1 and PRICKLE2 (608501) share 51.9% identity overall and 79.3% identity within the N-terminal PET and LIM domains. EST database analysis revealed coexpression of PRICKLE1 and PRICKLE2 in brain, eye, and testis; additionally, PRICKLE1 is expressed in fetal heart and in hematologic malignancies lymphoma and acute myelogenous leukemia (601626).
Bassuk et al. (2008) detected Prickle1 expression in neurons of several murine brain regions, including thalamus, hippocampus, cerebral cortex, and cerebellum.
Tao et al. (2011) demonstrated diffuse Prickle staining in neurons and neuronal structures in various regions of the Drosophila brain, including the optic lobes, central brain structures, and ventral segmental ganglia near the brain.
Using in situ hybridization and immunohistochemical analysis, Liu et al. (2013) found that mouse Pk1 was expressed during middle and late stages of cortical neurogenesis. In adult mouse brain, Pk1 was expressed widely, but in distinct neuronal and glial cell populations. In retina, highest Pk1 expression was detected in cholinergic amacrine neurons.
Shimojo and Hersh (2003) and Katoh and Katoh (2003) determined that the PRICKLE1 gene contains at least 8 exons. Katoh and Katoh (2003) determined that the 5-prime untranslated region is interrupted by intron 1.
By genomic sequence analysis, Shimojo and Hersh (2003) mapped the PRICKLE1 gene to chromosome 12q12. Katoh and Katoh (2003) mapped the human PRICKLE1 gene to chromosome 12q11-q12 and the mouse Prickle1 gene to chromosome 15.
By immunoprecipitation of transfected human embryonic kidney cells, Shimojo and Hersh (2003) demonstrated that PRICKLE1 interacts directly with REST. PRICKLE1 did not coimmunoprecipitate with a REST mutant in which the zinc finger structures were disrupted. Deletion analysis indicated that the C-terminal CIIS prenylation motif was necessary for targeting PRICKLE1 to the nucleus. Furthermore, downregulation of PRICKLE1 with small interfering RNAs (siRNAs) resulted in the mislocalization of REST to the cytosol.
Using yeast 2-hybrid and immunoprecipitation analyses, Shimojo (2008) showed that human RILP and huntingtin (HTT; 613004) interacted directly with dynactin-1 (DCTN1; 601143) to form a triplex. REST bound to the triplex through direct interaction with RILP, forming a quaternary complex involved in nuclear translocation of REST in non-neuronal cells. In neuronal cells, the complex also contained HAP1 (600947), which affected interaction of disease-causing mutant huntingtin, but not wildtype huntingtin, with dynactin-1 and RILP. Overexpression and knockout analyses demonstrated that the presence of HAP1 in the complex prevented nuclear translocation of REST and thereby regulated REST activity.
Liu et al. (2013) found that knockdown of Pk1 by short hairpin RNA or expression of dominant-negative constructs reduced axonal and dendritic extension in cultured mouse hippocampal neurons. Knockdown of Pk1 in neonatal mouse retina led to defects in inner and outer segments and axon terminals of photoreceptors.
Progressive Myoclonic Epilepsy 1B
In affected members of 3 Middle Eastern families with autosomal recessive progressive myoclonic epilepsy-1B (EPM1B; 612437), Bassuk et al. (2008) identified the same homozygous mutation in the PRICKLE1 gene (R104Q; 608500.0001). The findings were consistent with a founder effect.
Tao et al. (2011) identified 2 different heterozygous mutations in the PRICKLE1 gene (R144H, 608500.0002 and Y472H, 608500.0003, respectively) in 2 unrelated patients with myoclonic epilepsy. One patient had mild mental retardation, and no additional clinical information was provided for the other patient. No information on family members of either patient was provided. Tao et al. (2011) concluded that PRICKLE signaling is important in seizure prevention, and presented 2 hypotheses: (1) that PRICKLE affects cell polarity and contributes to the development of a functional neural network and (2) that PRICKLE affects calcium signaling, which may play a role in seizure genesis if disrupted.
Associations Pending Confirmation
Bosoi et al. (2011) identified 7 different heterozygous missense variants in the PRICKLE1 gene in 7 of 810 patients with a variety of neural tube defects (NTD; 182940). None of the variants were found in 1,396 controls, but the variants were inherited from an unaffected parent in 5 cases, suggesting incomplete penetrance. In silico analysis using PolyPhen software predicted that only 3 of the variants were probably damaging, whereas SIFT predicted that all were intolerant substitutions. Overexpression of the wildtype zebrafish ortholog (pk1a) results in defective convergent extension during gastrulation and neural tube formation. In zebrafish, Bosoi et al. (2011) found that overexpression of 5 of the variants found in humans resulted in more severe defects in convergent extension compared to wildtype, suggesting that they may act as hypermorphic alleles. Overexpression of 1 variant (R682C) rescued the effects of overexpressed Prickle1, suggesting a dominant-negative effect. Bosoi et al. (2011) hypothesized that variation in the PRICKLE1 gene may contribute to the development of neural tube defects in man.
Tao et al. (2011) found that Prickle1-mutant mice that were heterozygous for a C251X mutation, which truncates protein shortly after the PET and LIM domains, showed a decreased seizure threshold compared to wildtype mice. A similar phenotype was observed for Prickle1-mutant mice carrying a heterozygous F141S mutation, which alters an amino acid in the PET/LIM domain. These results suggested that disruption of the highly conserved PET/LIM domain is sufficient to lower seizure threshold. Homozygous Prickle1-null mice and homozygous C251X-mutant mice were embryonic lethal. In the Drosophila prickle mutant 'spiny legs-1,' pk(sple1)/pk(sple1) homozygous mutants showed severely decreased recovery in the bang test (sensitivity to vortexing), suggesting a decreased seizure threshold. A small percentage of pk(sple1)/pk(sple1) flies also showed generalized disorganization of the peripheral nervous system, with aberrant migration of neuronal processes resulting in improper connections; these changes were not observed in controls.
Ban et al. (2022) found that knockin mice carrying the Pk1 R104Q mutation (608500.0001) associated with progressive myoclonus epilepsy (EPM1B; 612437) in human had normal expression and stability of the Pk1 protein. However, the R104Q mutation impaired Pk1 function in assembly and maintenance of Psd95 (602887)-positive excitatory synapses in the hippocampus of mutant mice. The mutation is located within the highly conserved PET domain of Pk1, and fractionation analysis showed that R104Q impaired Pk1 interaction with Rest in vivo. Similar to humans, the R104Q mutation caused epileptic seizures in mice, with mice heterozygous for the mutation showing enhanced seizure susceptibility compared with mice homozygous for R104Q. Mutant mice also displayed impaired social approach behavior, but social recognition memory was normal. Anxiety level was unaltered in mutant mice. Cognitive functions test revealed that mice heterozygous for R104Q showed spatial memory deficit, whereas mice homozygous for the mutation displayed novel object recognition deficit.
In affected members of 3 unrelated consanguineous families with progressive myoclonic epilepsy-1B (EPM1B; 612437), Bassuk et al. (2008) identified a homozygous 311G-A transition in the PRICKLE1 gene, resulting in an arg104-to-gln (R104Q) substitution in a highly conserved region. The mutation was not detected in 1,354 control individuals. In vitro functional expression studies showed that mutant PRICKLE1 failed to bind REST (600571) and blocked transport of REST out of the nucleus, resulting in constitutive activation of REST and inappropriate downregulation of REST target genes.
In a male patient with EPM1B (612437), Tao et al. (2011) identified a heterozygous 431G-A transition in the PRICKLE1 gene, resulting in an arg144-to-his (R144H) substitution. The patient had myoclonic seizures, generalized EEG pattern, and mild mental retardation. No information regarding family members of this patient was provided. The mutation was not detected in 2,000 CEPH control chromosomes or 352 ethnically matched chromosomes.
In a female patient with juvenile myoclonic epilepsy (EPM1B; 612437), Tao et al. (2011) identified a heterozygous 1414T-C transition in the PRICKLE1 gene, resulting in a tyr472-to-his (Y472H) substitution. The authors provided no other clinical details on this patient or on any of her family members. The mutation was not detected in 2,000 CEPH control chromosomes or 352 ethnically matched chromosomes.
Ban, Y., Yu, T., Wang, J., Wang, X., Liu, C., Baker, C., Zou, Y. Mutation of the murine Prickle1 (R104Q) causes phenotypes analogous to human symptoms of epilepsy and autism. Exp. Neurol. 347: 113880, 2022. [PubMed: 34597683] [Full Text: https://doi.org/10.1016/j.expneurol.2021.113880]
Bassuk, A. G., Wallace, R. H., Buhr, A., Buller, A. R., Afawi, Z., Shimojo, M., Miyata, S., Chen, S., Gonzalez-Alegre, P., Griesbach, H. L., Wu, S., Nashelsky, M., and 18 others. A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome. Am. J. Hum. Genet. 83: 572-581, 2008. [PubMed: 18976727] [Full Text: https://doi.org/10.1016/j.ajhg.2008.10.003]
Bosoi, C. M., Capra, V., Allache, R., Trinh, V. Q.-H., De Marco, P., Merello, E., Drapeau, P., Bassuk, A. G., Kibar, Z. Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects. Hum. Mutat. 32: 1371-1375, 2011. [PubMed: 21901791] [Full Text: https://doi.org/10.1002/humu.21589]
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]
Liu, C., Lin, C., Whitaker, D., T., Bakeri, H., Bulgakov, O. V., Liu, P., Lei, J., Dong, L., Li, T., Swaroop, A. Prickle1 is expressed in distinct cell populations of the central nervous system and contributes to neuronal morphogenesis. Hum. Molec. Genet. 22: 2234-2246, 2013. [PubMed: 23420014] [Full Text: https://doi.org/10.1093/hmg/ddt075]
Shimojo, M., Hersh, L. B. REST/NRSF-interacting LIM domain protein, a putative nuclear translocation receptor. Molec. Cell. Biol. 23: 9025-9031, 2003. [PubMed: 14645515] [Full Text: https://doi.org/10.1128/MCB.23.24.9025-9031.2003]
Shimojo, M. Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150-Glued. J. Biol. Chem. 283: 34880-34886, 2008. [PubMed: 18922795] [Full Text: https://doi.org/10.1074/jbc.M804183200]
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]