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HGNC Approved Gene Symbol: PLCB1
Cytogenetic location: 20p12.3 Genomic coordinates (GRCh38) : 20:8,132,266-8,884,900 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p12.3 | Developmental and epileptic encephalopathy 12 | 613722 | Autosomal recessive | 3 |
Phospholipase C-beta (PLCB) catalyzes the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (IP2), a key step in the intracellular transduction of many extracellular signals. The PLCB1 gene encodes a mammalian PLCB isoform that is expressed in select areas of the brain, including cerebral cortex, hippocampus, amygdala, lateral septum, and olfactory bulb (summary by Koh et al., 2008).
Nagase et al. (1998) cloned PLCB1 from a brain cDNA library. The deduced protein shares approximately 96% identity with bovine PLCB1. Using rat and mouse PLCB1 sequences as query, Caricasole et al. (2000) identified an EST and a genomic clone corresponding to human PLCB1. They identified 2 variants, which they called PLCB1a and PLCB1b, derived from alternative splicing at the 3-prime end and encoding proteins of 1,173 and 1,216 amino acids, respectively. Northern blot analysis detected expression of a 7-kb transcript in neuroblastoma and hepatoma cell lines. PCR analysis detected expression of both isoforms in all tissues tested, at varying relative levels. Higher signal intensities were observed in some CNS areas, such as the amygdala, caudate nucleus, and hippocampus, and PLCB1a appeared to be expressed at slightly higher levels in most tissues. In comparison, PCR analysis of embryonic and adult rat tissues indicated restricted expression of both isoforms to embryonic and adult brain, with lower levels of expression in lung and testis. By confocal immunolocalization of endogenous or transfected epitope-tagged PLCB1, Caricasole et al. (2000) found that staining for both isoforms were similar and appeared mainly within the cytoplasm and at the plasma membrane, with some nuclear localization.
By screening a human fetal brain cDNA library with the rat PLCB1 sequence as probe, Peruzzi et al. (2000) cloned PLCB1. Northern blot analysis of fetal brain detected transcripts of 7.2 and 5.4 kb.
Caricasole et al. (2000) determined that the PLCB1 gene contains 32 exons and spans over 250 kb. Peruzzi et al. (2002) identified an additional exon at the 5-prime end.
By radiation hybrid analysis, Nagase et al. (1998) mapped the PLCB1 gene to chromosome 20. Based on sequence identity with a PAC clone, Caricasole et al. (2000) mapped the gene to 20p12. They confirmed the localization to chromosome 20 by PCR screening of a monochromosomal hybrid panel. Peruzzi et al. (2000) mapped the gene to 20p12 by FISH.
Lo Vasco et al. (2004) stated that the PLCB1 protein is present in the nucleus and is involved in control of the cell cycle. Using FISH analysis, they studied 11 patients with myelodysplastic syndrome (MDS) and 9 with acute myeloid leukemia (AML) for changes in the PLCB1 gene. MDS evolves into AML in about 30% of patients, and those MDS patients with chromosomal rearrangement are usually thought to be at greater risk for development of AML, but there are many exceptions. In 2 MDS patients and 3 AML patients with chromosomal rearrangements involving chromosome 20, Lo Vasco et al. (2004) detected a monoallelic loss of the PLCB1 gene. Four of 9 MDS patients with normal karyotypes had monoallelic deletion of the PLCB1 gene, and all 4 died within 1 to 6 months after developing AML, compared to survival of over 30 months in the 5 MDS patients without the deletion. Two of 6 AML patients with normal karyotypes had monoallelic deletion of the PLCB1 gene; these 2 patients had a reduced survival (1 to 12 months) compared to the AML patients without the deletion (20 to 29 months). Lo Vasco et al. (2004) suggested a role for PLCB1 in MDS disease progression.
Developmental and Epileptic Encephalopathy 12
By genomewide scanning of a patient with developmental and epileptic encephalopathy-12 (DEE12; 613722), Kurian et al. (2010) identified a homozygous 0.5-Mb deletion on chromosome 20p12 encompassing the promoter element and exons 1, 2, and 3 of the PLCB1 gene (607120.0001), resulting in loss of PLCB1 expression. No other coding genes were involved in the deletion, which was not found in 660 control chromosomes. The telomeric and centromeric genomic breakpoints were mapped to 8,034,442-8,034,510 bp and 8,520,654-8,520,722 bp, respectively. Each unaffected parent was heterozygous for the deletion. The patient had early-onset seizures, evolving to refractory seizures and regression in all areas of development. By 13 months, EEG showed features of West syndrome, hypsarrhythmia, and generalized slowing, consistent with a diffuse encephalopathic process.
In a patient, born of consanguineous Palestinian parents, with DEE12 manifest clinically as malignant migrating partial seizures in infancy (MMPSI), Poduri et al. (2012) identified a homozygous 486-kb deletion on chromosome 20p12.3 encompassing the promoter region and exons 1, 2, and 3 of the PLCB1 gene (607120.0001). The deletion breakpoints were mapped to 8,094,049-8,094,072 to 8,580,261-8,580,284 (GRCh37). The breakpoints lie within 2 LINE nuclear elements and likely arose from nonallelic homologous recombination. Poduri et al. (2012) considered the disorder in this patient to be electroclinically distinct from that of the patient described by Kurian et al. (2010), who had a normal initial EEG and later developed hypsarrhythmia. PLCB1 mutations were not found by Poduri et al. (2012) in 18 index patients with a phenotype consistent with MMPSI.
Kim et al. (1997) found that Plcb1-null mice showed retarded growth and low viability after birth and developed recurrent tonic-clonic seizures, often dying of status epilepticus. Loss of Plcb1 in the brain was associated with impaired signaling via muscarinic acetylcholine receptors (mAChR), and histochemical analysis of the hippocampus showed selective loss of somatostatin-containing interneurons from the hilus. These findings suggested that the seizures were evoked through hyperexcitability of the hippocampus.
Koh et al. (2008) found that Plcb1-null mice showed various endophenotypes regarded as relevant to schizophrenia in humans. Plcb1-null mice showed hyperactivities in an open field and abnormal social behaviors, such as lack of barbering behavior, socially recessive trait, and lack of nesting behavior. Mutant mice also showed defects in sensorimotor gating as shown by impaired prepulse inhibition of acoustic startle response that was ameliorated by the antipsychotic D2-receptor antagonist haloperidol. Defects in learning and memory were also present. These mutant mice thus shared some of the endophenotypes related to the 3 categories of symptoms of schizophrenia in humans: positive, negative, and cognitive.
McOmish et al. (2008) found that Plcb1-null mice showed deficits in working memory and disrupted fear conditioning compared to wildtype mice. In situ hybridization studies showed decreased expression of Rgs4 (602516), which interacts with and regulates Plcb1, in the CA1 region of the hippocampus in mutant mice compared to wildtype mice. These findings further suggested that Plcb1-null mice may be a good model for disrupted cortical development and plasticity with behavioral endophenotypes similar to schizophrenia.
In a boy, born of consanguineous parents from Bangladesh, with developmental and epileptic encephalopathy-12 (DEE12; 613722), Kurian et al. (2010) identified a homozygous 0.5-Mb deletion encompassing the promoter element and exons 1, 2, and 3 of the PLCB1 gene, resulting in loss of PLCB1 expression. No other coding genes were involved in the deletion, which was not found in 660 control chromosomes. The telomeric and centromeric genomic breakpoints were mapped to 8,034,442-8,034,510 bp and 8,520,654-8,520,722 bp, respectively. Each unaffected parent was heterozygous for the deletion. The patient had early-onset seizures, evolving to refractory seizures and regression in all areas of development. By 13 months, EEG showed features of West syndrome, hypsarrhythmia, and generalized slowing, consistent with a diffuse encephalopathic process.
In a patient, born of consanguineous Palestinian parents, with DEE12 who presented with a clinical diagnosis of malignant migrating partial seizures in infancy (MMPSI), Poduri et al. (2012) identified a homozygous 486-kb deletion on chromosome 20p12.3 encompassing the promoter region and exons 1, 2, and 3 of the PLCB1 gene. The deletion breakpoints were mapped to 8,094,049-8,094,072 to 8,580,261-8,580,284 (GRCh37). The breakpoints lie within 2 LINE nuclear elements and likely arose from nonallelic homologous recombination. The patient had onset of focal seizures at age 6 months and thereafter showed developmental regression. EEG showed multifocal interictal spikes and abundant seizures arising from both hemispheres and showing migration from one hemisphere to another within a seizure. Poduri et al. (2012) considered the disorder to be electroclinically distinct from that in the patient described by Kurian et al. (2010), who had a normal initial EEG and later developed hypsarrhythmia.
Caricasole, A., Sala, C., Roncarati, R., Formenti, E., Terstappen, G. C. Cloning and characterization of the human phosphoinositide-specific phospholipase C-beta-1 (PLC-beta-1). Biochim. Biophys. Acta 1517: 63-72, 2000. [PubMed: 11118617] [Full Text: https://doi.org/10.1016/s0167-4781(00)00260-8]
Kim, D., Jun, K. S., Lee, S. B., Kang, N.-G., Min, D. S., Kim, Y.-H., Ryu, S. H., Suh, P.-G., Shin, H.-S. Phospholipase C isozymes selectively couple to specific neurotransmitter receptors. Nature 389: 290-293, 1997. [PubMed: 9305844] [Full Text: https://doi.org/10.1038/38508]
Koh, H.-Y., Kim, D., Lee, J., Lee, S., Shin, H.-S. Deficits in social behavior and sensorimotor gating in mice lacking phospholipase C-beta-1. Genes Brain Behav. 7: 120-128, 2008. [PubMed: 17696993] [Full Text: https://doi.org/10.1111/j.1601-183X.2007.00351.x]
Kurian, M. A., Meyer, E., Vassallo, G., Morgan, N. V., Prakash, N., Pasha, S., Hai, N. A., Shuib, S., Rahman, F., Wassmer, E., Cross, J. H., O'Callaghan, F. J., Osborne, J. P., Scheffer, I. E., Gissen, P., Maher, E. R. Phospholipase C-beta-1 deficiency is associated with early-onset epileptic encephalopathy. Brain 133: 2964-2970, 2010. [PubMed: 20833646] [Full Text: https://doi.org/10.1093/brain/awq238]
Lo Vasco, V. R., Calabrese, G., Manzoli, L., Palka, G., Spadano, A., Morizio, E., Guanciali-Franchi, P., Fantasia, D., Cocco, L. Inositide-specific phospholipase C-beta-1 gene deletion in the progression of myelodysplastic syndrome to acute myeloid leukemia. Leukemia 18: 1122-1126, 2004. [PubMed: 15085153] [Full Text: https://doi.org/10.1038/sj.leu.2403368]
McOmish, C. E., Burrows, E. L., Howard, M., Hannan, A. J. PLC-beta-1 knockout mice as a model of disrupted cortical development and plasticity: behavioral endophenotypes and dysregulation of RGS4 gene expression. Hippocampus 18: 824-834, 2008. [PubMed: 18493969] [Full Text: https://doi.org/10.1002/hipo.20443]
Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]
Peruzzi, D., Aluigi, M., Manzoli, L., Billi, A. M., Di Giorgio, F. P., Morleo, M., Martelli, A. M., Cocco, L. Molecular characterization of the human PLC-beta-1 gene. Biochim. Biophys. Acta 1584: 46-54, 2002. [PubMed: 12213492] [Full Text: https://doi.org/10.1016/s1388-1981(02)00269-x]
Peruzzi, D., Calabrese, G., Faenza, I., Manzoli, L., Matteucci, A., Gianfrancesco, F., Billi, A. M., Stuppia, L., Palka, G., Cocco, L. Identification and chromosomal localisation by fluorescence in situ hybridisation of human gene of phosphoinositide-specific phospholipase C-beta-1. Biochim. Biophys. Acta 1484: 175-182, 2000. [PubMed: 10760467] [Full Text: https://doi.org/10.1016/s1388-1981(00)00012-3]
Poduri, A., Chopra, S. S., Neilan, E. G., Elhosary, P. C., Kurian, M. A., Meyer, E., Barry, B. J., Khwaja, O. S., Salih, M. A. M., Stodberg, T., Scheffer, I. E., Maher, E. R., Sahin, M., Wu, B.-L., Berry, G. T., Walsh, C. A., Picker, J., Kothare, S. V. Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy. Epilepsia 53: e146-e150, 2012. Note: Electronic Article. [PubMed: 22690784] [Full Text: https://doi.org/10.1111/j.1528-1167.2012.03538.x]