HGNC Approved Gene Symbol: PLCB3
SNOMEDCT: 1269226006;
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:64,251,530-64,269,452 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | Spondylometaphyseal dysplasia with corneal dystrophy | 618961 | Autosomal recessive | 3 |
PLCB3 plays an important role in initiating receptor-mediated signal transduction. Activation of PLC takes place in many cells as a response to stimulation by hormones, growth factors, neurotransmitters, and other ligands (Lagercrantz et al., 1995).
Weber et al. (1994) mapped the gene for multiple endocrine neoplasia type I (MEN1; 131100) to a region of less than 900 kb by deletion mapping in 27 primary parathyroid tumors. One of the cDNA clones isolated from this region showed expression of a 4.4-kb message in multiple tissues, including those affected in MEN1, while in 5 endocrine tumors from MEN1 patients no transcript was detected. Sequence characterization showed that this gene encodes PLCB3, a key enzyme in signal transduction.
Lagercrantz et al. (1995) determined that the full-length PLCB3 cDNA has an open reading frame of 1,234 amino acids. Northern blot analysis revealed a 4.4-kb transcript in all tissues tested.
Mazuruk et al. (1995) cloned the PLCB3 gene. It was highly expressed in several human tissues, including retina, brain, and kidney. PLCB3 mRNA was detected at a much lower level in liver.
Lagercrantz et al. (1995) estimated that the size of the complete PLCB3 transcription unit is on the order of 15 kb. The gene contains 31 exons, with all splice donor and acceptor sites conforming to the GT/AG rule. No exon exceeds 571 bp in length, and the shortest exon spans only 36 bp. More than half of the introns are shorter than 200 bp, with the shortest being only 79 bp.
Mazuruk et al. (1995) determined that the PLCB3 gene spans approximately 17 kb and contains 31 exons.
Crystal Structure
Waldo et al. (2010) described how heterotrimeric guanine nucleotide-binding proteins (G proteins) activate PLC-betas and in turn are deactivated by the downstream effectors. The 2.7-angstrom structure of PLC-beta-3 bound to activated G-alpha-q (600998) revealed a conserved module found within PLC-betas and other effectors optimized for rapid engagement of activated G proteins. The active site of PLC-beta-3 in the complex is occluded by an intramolecular plug that is likely removed upon G protein-dependent anchoring and orientation of the lipase at membrane surfaces. A second domain of PLC-beta-3 subsequently accelerates guanosine triphosphate hydrolysis by G-alpha-q, causing the complex to dissociate and terminate signal propagation. Mutations within this domain dramatically delay signal termination in vitro and in vivo. Waldo et al. (2010) concluded that their work suggested a dynamic catch-and-release mechanism used to sharpen spatiotemporal signals mediated by diverse sensory inputs.
In the course of the molecular characterization of a human extragonadal germ cell tumor (EGCT)-associated chromosomal translocation, Sinke and Geurts van Kessel (1995) identified YACs and cosmids from the 11q13 region. The end clone of one of these YACs appeared to contain a stretch of DNA homologous to part of the PLCB3 gene. They cloned the entire cDNA and confirmed the location of the gene to 11q13. No aberrantly hybridizing fragments were observed in EGCT DNAs. This result, together with mRNA studies, excluded the PLCB3 gene as a candidate in the development of EGCTs.
Courseaux et al. (1996) used a combination of methods to refine maps of the approximately 5-Mb region of 11q13 that includes MEN1. They proposed the following gene order: cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1--[MLK3, RELA]--FOSL1--SEA--CFL1--tel.
Gobl et al. (1995) mapped the Plcb3 gene to mouse chromosome 19.
Because of its chromosomal localization and biologic function, Mazuruk et al. (1995) considered PLCB3 to be a promising candidate for human genetic disorders such as Bardet-Biedl syndrome type 1 (BBS1; see 209900), Best disease (153700), and 2 forms of vitreoretinopathy (193235, 133780). Because of its map location on 11q13, its function in the signal transduction cascade, and its expression pattern, PLCB3 was considered an attractive candidate for the site of the mutation in multiple endocrine neoplasia type I (131100) but was excluded as a candidate for this disorder by failure to find mutations (Weber et al., 1997; de Wit et al., 1997).
In 2 affected cousins from a consanguineous Emirati family with spondylometaphyseal dysplasia with corneal dystrophy (SMDCD; 618961), Ben-Salem et al. (2018) identified homozygosity for a missense mutation in the PLCB3 gene (A878S; 600230.0001) that segregated with disease and was not found in 200 ethnically matched control chromosomes. Functional analysis showed that A878S is a hypomorphic variant that results in accumulation of the PLCB3 substrate PIP(2) and causes dysregulation of the actin cytoskeleton in patient fibroblasts.
Morphine and other mu opioids regulate a number of intracellular signaling pathways, including the one mediated by PLC. By studying Plcb3-deficient mice, Xie et al. (1999) established a strong link between PLC and mu-opioid-mediated responses at both the behavioral and the cellular levels. When compared with the wildtype, mice lacking Plcb3 exhibited up to a 10-fold decrease in the ED50 value for morphine in producing antinociception. The reduced ED50 value was unlikely to be a result of changes in opioid receptor number or affinity because no differences were found in whole brain Bmax and Kd values for mu-, kappa-, and delta-opioid receptors between wildtype and Plcb3 null mice. Xie et al. (1999) demonstrated that PLCB3 constitutes a significant pathway involved in negative modulation of mu-opioid responses, perhaps via protein kinase C (see 176982), and suggested that differences in opioid sensitivity among individuals could be, in part, because of genetic factors. They noted that Wang et al. (1998) had reported that a targeted disruption of the Plcb3 gene caused embryonic lethality. The fact that their construct deleted exons 11 to 17, whereas the construct used by Xie et al. (1999) partially deleted 1 exon, may account for the absence of lethality in the animals studied by Xie et al. (1999).
Li et al. (2000) studied mice lacking Plcb3. These mice developed spontaneous multifocal skin ulcers usually starting at the age of 6 months or older. The lesions were localized mainly behind ears or on the neck, but sometimes also appeared on the face. A similar phenotype was observed in mice lacking both Plcb2 (604114) and Plcb3. Histologic examination of the lesion tissues revealed hyperinfiltration of leukocytes in the lesion tissues. Most leukocytes were macrophages or lymphocytes.
Using mice lacking either Plcb2, Plcb3, or both Plcb2 and Plcb3, Wang et al. (2008) identified Plcb3 as the major functional isoform in mouse macrophages. Plcb3 deficiency did not affect macrophage migration, adhesion, or phagocytosis, but it resulted in hypersensitivity to several inducers of apoptosis via upregulation of Pkc (see 176960)-dependent upregulation of Bclxl (600039). In the apoE (107741)-deficient mouse model of atherosclerosis, mice lacking both apoE and Plcb3 exhibited fewer total macrophages and increased macrophage apoptosis in atherosclerotic lesions and reduced lesion size compared with mice lacking only apoE. Wang et al. (2008) concluded that PLC activity is critical for promoting macrophage survival in atherosclerotic plaques.
In 2 affected cousins from a consanguineous Emirati family with spondylometaphyseal dysplasia with corneal dystrophy (SMDCD; 618961), Ben-Salem et al. (2018) identified homozygosity for a c.2632G-T transversion (c.2632G-T, NM_000932.2) in the PLCB3 gene, resulting in an ala878-to-ser (A878S) substitution at a highly conserved residue within the autoinhibitory Ha2-prime helix element in the proximal C-terminal domain. The mutation segregated with disease in the family and was not found in 200 ethnically matched control chromosomes or in the dbSNP or EVS databases. However, it was present at low minor allele frequency (MAF) in heterozygous state in the ExAC database (0.00001.82). Together with a second heterozygous variant at the same nucleotide (c.2632G-A; A878T), the total multiallelic variance at c.2632 had a frequency of 0.00006.385 in the ExAC database. Western blot of cells lysates from transiently transfected COS7 cells showed a 95% reduction in mutant protein levels compared to wildtype PLCB3. Immunofluorescence assays demonstrated a marked increase in levels of the PLCB3 substrate PIP(2) in patient fibroblasts compared to controls, as well as nuclear aggregation of PIP(2) that was not seen in control fibroblasts. Immunostaining of lectin fibers showed that patient fibroblasts were significantly larger than those of controls. Quantification of F-actin (see 102610) staining in patient fibroblasts showed a significant overall decrease in actin network strength compared with normal fibroblasts, and the staining was more punctate, highlighting very short fibers. Patient fibroblasts also showed increased sensitivity to stress compared to control fibroblasts.
Ben-Salem, S., Robbins, S. M., Sobreira, N. L. M., Lyon, A., Al-Shamsi, A. M., Islam, B. K., Akawi, N. A., John, A., Thachillath, P., Al Hamed, S., Valle, D., Ali, B. R., Al-Gazali, L. Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy. J. Med. Genet. 55: 122-130, 2018. [PubMed: 29122926] [Full Text: https://doi.org/10.1136/jmedgenet-2017-104827]
Courseaux, A., Grosgeorge, J., Gaudray, P., Pannett, A. A. J., Forbes, S. A., Williamson, C., Bassett, D., Thakker, R. V., Teh, B. T., Farnebo, F., Shepherd, J., Skogseid, B., Larsson, C., Giraud, S., Zhang, C. X., Salandre, J., Calender, A. Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13. Genomics 37: 354-365, 1996. [PubMed: 8938448]
de Wit, M. J., Landsvater, R. M., Sinke, R. J., Geurts van Kessel, A., Lips, C. J. M., Hoppener, J. W. M. Exclusion of the phosphatidylinositol-specific phospholipase C beta-3 (PLC beta-3) gene as candidate for the multiple endocrine neoplasia type 1 (MEN 1) gene. Hum. Genet. 99: 133-137, 1997. [PubMed: 9003511] [Full Text: https://doi.org/10.1007/s004390050327]
Gobl, A. E., Chowdhary, B. P., Shu, W., Eriksson, L., Larsson, C., Weber, G., Oberg, K., Skogseid, B. Assignment of the mouse homologue of a human MEN1 candidate gene, phospholipase C-beta-3 (Plcb3), to chromosome region 19B by FISH. Cytogenet. Cell Genet. 71: 257-259, 1995. [PubMed: 7587389] [Full Text: https://doi.org/10.1159/000134122]
Lagercrantz, J., Carson, E., Phelan, C., Grimmond, S., Rosen, A., Dare, E., Nordenskjold, M., Hayward, N. K., Larsson, C., Weber, G. Genomic organization and complete cDNA sequence of the human phosphoinositide-specific phospholipase C beta-3 gene (PLCB3). Genomics 26: 467-472, 1995. [PubMed: 7607669] [Full Text: https://doi.org/10.1016/0888-7543(95)80164-h]
Li, Z., Jiang, H., Xie, W., Zhang, Z., Smrcka, A. V., Wu, D. Roles of PLC-beta-2 and -beta-3 and PI3K-gamma in chemoattractant-mediated signal transduction. Science 287: 1046-1049, 2000. [PubMed: 10669417] [Full Text: https://doi.org/10.1126/science.287.5455.1046]
Mazuruk, K., Schoen, T. J., Chader, G. J., Rodriguez, I. R. Structural organization and expression of the human phosphatidylinositol-specific phospholipase C beta-3 gene. Biochem. Biophys. Res. Commun. 212: 190-195, 1995. [PubMed: 7612006] [Full Text: https://doi.org/10.1006/bbrc.1995.1955]
Sinke, R. J., Geurts van Kessel, A. Localization of the human phosphatidylinositol-specific phospholipase C beta-3 gene (PLCB3) within chromosome band 11q13. Genomics 25: 568-569, 1995. [PubMed: 7789993] [Full Text: https://doi.org/10.1016/0888-7543(95)80060-y]
Waldo, G. L., Ricks, T. K., Hicks, S. N., Cheever, M. L., Kawano, T., Tsuboi, K., Wang, X., Montell, C., Kozasa, T., Sondek, J., Harden, T. K. Kinetic scaffolding mediated by a phospholipase C-beta and G-q signaling complex. Science 330: 974-980, 2010. [PubMed: 20966218] [Full Text: https://doi.org/10.1126/science.1193438]
Wang, S., Gebre-Medhin, S., Betsholtz, C., Stalberg, P., Zhou, Y., Larsson, C., Weber, G., Feinstein, R., Oberg, K., Gobl, A., Skogseid, B. Targeted disruption of the mouse phospholipase C beta-3 gene results in early embryonic lethality. FEBS Lett. 441: 261-265, 1998. [PubMed: 9883896] [Full Text: https://doi.org/10.1016/s0014-5793(98)01518-x]
Wang, Z., Liu, B., Wang, P., Dong, X., Fernandez-Hernando, C., Li, Z., Hla, T., Li, Z., Claffey, K., Smith, J. D., Wu, D. Phospholipase C beta-3 deficiency leads to macrophage hypersensitivity to apoptotic induction and reduction of atherosclerosis in mice. J. Clin. Invest. 118: 195-204, 2008. [PubMed: 18079968] [Full Text: https://doi.org/10.1172/JCI33139]
Weber, G., Friedman, E., Grimmond, S., Hayward, N. K., Phelan, C., Skogseid, B., Gobl, A., Zedenius, J., Sandelin, K., Teh, B. T., Carson, E., White, I., Oberg, K., Shepherd, J., Nordenskjold, M., Larsson, C. The phospholipase C beta-3 gene located in the MEN1 region shows loss of expression in endocrine tumours. Hum. Molec. Genet. 3: 1775-1781, 1994. [PubMed: 7849701] [Full Text: https://doi.org/10.1093/hmg/3.10.1775]
Weber, G., Grimmond, S., Lagercrantz, J., Friedman, E., Phelan, C., Carson, E., Hayward, N., Jacobvitz, O., Nordenskjold, M., Larsson, C. Exclusion of the phosphoinositide-specific phospholipase C-beta-3 (PLCB3) gene as a candidate for multiple endocrine neoplasia type 1. Hum. Genet. 99: 130-132, 1997. [PubMed: 9003510] [Full Text: https://doi.org/10.1007/s004390050326]
Xie, W., Samoriski, G. M., McLaughlin, J. P., Romoser, V. A., Smrcka, A., Hinkle, P. M., Bidlack, J. M., Gross, R. A., Jiang, H., Wu, D. Genetic alteration of phospholipase C beta-3 expression modulates behavioral and cellular responses to mu opioids. Proc. Nat. Acad. Sci. 96: 10385-10390, 1999. [PubMed: 10468617] [Full Text: https://doi.org/10.1073/pnas.96.18.10385]