Alternative titles; symbols
HGNC Approved Gene Symbol: PLCE1
Cytogenetic location: 10q23.33 Genomic coordinates (GRCh38): 10:93,993,931-94,332,823 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.33 | Nephrotic syndrome, type 3 | 610725 | Autosomal recessive | 3 |
PLCE1 belongs to the phospholipase family that catalyzes the hydrolysis of polyphosphoinositides such as phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to generate the second messengers Ins(1,4,5)P3 and diacylglycerol. These products initiate a cascade of intracellular responses that result in cell and differentiation and gene expression. In addition, PLCE1 activates the small G protein Ras/mitogen-activated protein kinase (MAPK) signaling pathway (summary by Lopez et al., 2001).
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (2000) cloned PLCE1, which they designated KIAA1516. The 3-prime untranslated region of the transcript contains a MIR repeat sequence. The deduced 1,609-amino acid protein shares 32% identity with C. elegans PLC210. RT-PCR ELISA detected moderate expression in all tissues and specific brain regions examined. Highest expression was in pancreas and spinal cord, and lowest expression was in skeletal muscle, ovary, and adult and fetal liver.
Using the conserved X and Y domains of mammalian PLCs to query an EST database, followed by 5-prime RACE of a heart cDNA library, Lopez et al. (2001) cloned PLCE1. The deduced 1,994-amino acid protein has a calculated molecular mass of 230 kD. PLCE1 contains an N-terminal HRAS (190020) guanine exchange factor (RAS-GEF) domain, followed by central catalytic X and Y domains, a regulatory C2 domain, and 2 C-terminal HRAS-associating (RA) domains. Northern blot analysis detected a transcript of about 7.5 kb in a wide variety of tissues, including brain, lung, kidney, testis, and colon, with highest expression in heart. A transcript of about 9.5 kb was also detected in most tissues. Cell fractionation and Western blot analysis of transfected TSA201 human embryonic kidney cells indicated that PLCE1 partitioned in the particulate fraction and showed an apparent molecular mass of 230 kD.
By searching an EST database for sequences similar to C. elegans PLC210, followed by 5-prime RACE of a fetal brain cDNA library, Song et al. (2001) cloned PLCE1. The deduced protein contains 2,303 amino acids. The authors noted that, unlike other PLCs, PLCE1 lacks a pleckstrin homology domain and an EF-hand motif.
Crystal Structure
By nuclear magnetic resonance and x-ray crystallography, Bunney et al. (2006) solved the structures of the 2 isolated C-terminal RA domains (RA1 and RA2) of mammalian Plce1 and the structure of the RA2/Ras complex, respectively. Although both contain ubiquitin-like folds, only RA2 bound Ras. Bunney et al. (2006) predicted that RA2 targets Plce1 to membranes and may also function as an inhibitory domain depending on Plce1 conformation.
Hinkes et al. (2006) stated that the PLCE1 gene extends over 334.4 kb and contains 34 exons.
The International Radiation Hybrid Mapping Consortium mapped the PLCE1 gene to chromosome 10 (STS-N32898). By Southern blot analysis, Lopez et al. (2001) determined that PLCE1 is a single-copy gene. Hinkes et al. (2006) found mutations at the PLCE1 gene in a form of nephrotic syndrome that maps to 10q23.32-q24.1.
Lopez et al. (2001) confirmed that PLCE1 contained in plasma membranes of transfected TSA201 cells showed PLC activity against PtdIns(4,5)P2, the selective PLC substrate. Cotransfection of a constitutively active form of the heterotrimeric G protein GNA12 (604394) stimulated PLCE1-mediated hydrolysis of polyphosphoinositides nearly 3-fold. Further, PLCE1 and a his1144-to-leu mutant (H1144L) incapable of hydrolyzing phosphoinositides promoted formation of GTP-HRAS, indicating that PLCE1 is a RAS-GEF. PLCE1, the H1144L mutant, and the isolated N-terminal GEF domain activated the mitogen-activated protein kinase (MAPK) pathway in a manner dependent on HRAS but independent of PtdIns(4,5)P2 hydrolysis. Lopez et al. (2001) concluded that PLCE1 is a bifunctional enzyme that is regulated by GNA12 and activates the RAS/MAPK signaling pathway.
Song et al. (2001) determined that PLCE1 expressed in insect cells showed Ca(2+)-dependent hydrolysis of PtdIns(4,5)P2, with maximal activity obtained at 10 micromolar Ca(2+). In a liposome-based reconstitution assay, the ability of PLCE1 to hydrolyze PtdIns(4,5)P2 was stimulated by HRAS in a GTP-dependent manner. The isolated RA domain associated with the GTP-bound forms of HRAS and RAP1A (179520) and inhibited HRAS-dependent adenylyl cyclase activity. Coexpression of an activated HRAS mutant with PLCE1 in COS-7 cells induced the translocation of PLCE1 from the cytosol to the plasma membrane. EGF (131530) also stimulated the translocation of PLCE1 to the plasma membrane, and this stimulation was inhibited by coexpression of a dominant-negative HRAS. Song et al. (2001) concluded that HRAS directly regulates phosphoinositide breakdown through membrane targeting of PLCE1.
Song et al. (2002) presented evidence that both RAP1 and HRAS regulated PLCE1 following stimulation of PDGF receptor (see PDGFRB; 173410) in COS-7 cells. HRAS mediated the rapid and transient signal for the activation of PLCE1, and RAP1 was responsible for the sustained activation. The CDC25 (157680) homology domain of PLCE1, which exhibited RAP1-specific GEF activity, was critical for the prolonged PLCE1 activation in RAP1-dependent signaling.
Evellin et al. (2002) demonstrated that the M3 muscarinic acetylcholine receptor (118494) can stimulate PLCE1. Stimulation was apparently mediated by stimulatory G protein (see 139320)-dependent formation of cyclic AMP and the subsequent activation of the GTPase RAP2B (179541).
Nephrotic Syndrome, Type 3
Hinkes et al. (2006) analyzed the PLCE1 gene in 7 consanguineous kindreds with early-onset nephrotic syndrome (NPHS3; 610725) and homozygosity for microsatellites at the NPHS3 locus on chromosome 10q23.32-q24.1 and identified 6 different homozygous truncating mutations (608414.0001-608414.0006) and 1 homozygous missense mutation (608414.0007). Individuals with truncating mutations had an earlier onset of disease and diffuse mesangial sclerosis (DMS) on renal biopsy; the 2 sibs who were homozygous for the missense mutation had later onset of disease and focal segmental glomerulosclerosis (FSGS) on renal biopsy.
Boyer et al. (2010) identified homozygous or compound heterozygous mutations in the PLCE1 gene (see, e.g., 608414.0008-608414.0010) in affected individuals from 12 (18%) of 68 families with steroid-resistant nephrotic syndrome and 3 (7%) of 44 patients with sporadic disease. Among the 12 families, renal biopsy showed FSGS in 6 and DMS in 5; 1 family had no biopsy results. There were no apparent genotype/phenotype correlations, but patients with DMS had a worse prognosis compared to those with FSGS. However, 3 unrelated individuals who were not affected were found to carry homozygous mutations that caused disease in their respective families, suggesting that additional factors are necessary to disease to occur.
Associations Pending Confirmation
For discussion of a possible association between variation in the PLCE1 gene and susceptibility to esophageal squamous cell carcinoma and gastric cardia adenocarcinoma, see 133239.
In a patient with early-onset nephrotic syndrome (NPHS3; 610725), Hinkes et al. (2006) identified homozygosity for a 1-bp deletion (1146delG) in exon 2 of the PLCE1 gene, causing a frameshift resulting in a termination signal at codon 387. Onset of disease was 4 months of age, and the patient had end-stage renal disease by 5 months of age.
In 2 Israeli sibs with early-onset nephrotic syndrome (NPHS3; 610725) and consanguineous parents, Hinkes et al. (2006) identified homozygosity for a 1477C-T transition in exon 3 of the PLCE1 gene, resulting in an arg493-to-ter (R493X) substitution. One sib developed symptoms at age 4 months, did not respond to steroid treatment, and had end-stage renal disease at 10 months of age. The other sib, who developed symptoms at 2 months of age, was also steroid-resistant but responded to cyclosporin A, and remained free of proteinuria at 13 years of age under treatment with an angiotensin-converting enzyme inhibitor for hypertension. Kidney biopsy at age 7 months and 5 months, respectively, showed diffuse mesangial sclerosis in both patients.
In 2 Turkish sibs with early-onset nephrotic syndrome (NPHS3; 610725) and consanguineous parents, Hinkes et al. (2006) identified homozygosity for a 3346C-T transition in exon 10 of the PLCE1 gene, resulting in an arg1116-to-ter (R1116X) substitution. The older sib had onset of disease at 4 years of age, did not respond to steroid treatment, and had end-stage renal disease (ESRD) at 5 years of age; the younger developed symptoms at 2 years of age and was found to have ESRD. Kidney biopsy at age 4.5 years and 2 years, respectively, showed diffuse mesangial sclerosis in both patients as well as ESRD in the older sib.
In 2 Turkish sibs with early-onset nephrotic syndrome (NPHS3; 610725) and consanguineous parents, Hinkes et al. (2006) identified homozygosity for a 1-bp deletion (3843delG) in exon 14 of the PLCE1 gene, causing a frameshift resulting in a termination signal at codon 1308. End-stage kidney disease was discovered at age 3 years and 6 months, respectively; kidney biopsy in the older sib revealed diffuse mesangial sclerosis.
In 2 Turkish sibs with early-onset nephrotic syndrome (NPHS3; 610725) and consanguineous parents, Hinkes et al. (2006) identified homozygosity for a 4846C-T transition in exon 21 of the PLCE1 gene, resulting in a gln1616-to-ter (Q1616X) substitution. The sibs developed steroid-resistant end-stage renal disease by age 1 year and 8 months, respectively; kidney biopsies at age 8 months and 7 months, respectively, revealed diffuse mesangial sclerosis (DMS) in the older sib and DMS and focal and segmental glomerulosclerosis (FSGS) in the younger.
In 2 Turkish sibs and a related individual with early-onset nephrotic syndrome (NPHS3; 610725) and consanguineous parents, Hinkes et al. (2006) identified homozygosity for a 5560C-T transition in the PLCE1 gene, resulting in a gln1854-to-ter (Q1854X) substitution. The older sib, who developed symptoms at age 12 months, responded to an 8-month course of steroids and remained virtually free of symptoms. At age 6 years, he had normal serum albumin and creatinine and a near-normal protein/creatinine ratio (0.37). The related individual from an earlier generation had onset of disease at age 8 months and died of end-stage renal disease at 11 months of age; kidney biopsy at 11 months showed diffuse mesangial sclerosis.
In 2 Turkish sibs with early-onset nephrotic syndrome (NPHS3; 610725) and consanguineous parents, Hinkes et al. (2006) identified homozygosity for a 4451C-T transition in exon 18 of the PLCE1 gene, resulting in a ser1484-to-leu (S1484L) substitution. Onset of disease in the sibs was 8.8 years and 2 years of age, respectively, with development of end-stage renal disease by 12 years and 4 years of age, respectively. Both sibs were resistant to treatment with steroids and cyclophosphamide; kidney biopsy at age 8.9 years and 4.6 years, respectively, showed focal and segmental glomerulosclerosis (FSGS) in both.
In a girl, born of consanguineous Turkish parents, with NPHS3 (NPHS3; 610725), Boyer et al. (2010) identified a homozygous 6448C-T transition in exon 30 of the PLCE1 gene, resulting in an arg2150-to-ter (R2150X) substitution. She developed nephrotic syndrome at age 11 months and end-stage renal disease at age 2.7 years; renal biopsy showed diffuse mesangial sclerosis. Of note, a brother who was also homozygous for the mutation had no proteinuria at age 10 years, suggesting the presence of modifying factors.
In 2 sibs, born of consanguineous Pakistani parents, with NPHP3 (NPHS3;610725), Boyer et al. (2010) identified a homozygous 961C-T transition in exon 2 of the PLCE1 gene, resulting in an arg321-to-ter (R321X) substitution. Age at onset was 3 years and 5 months, respectively, and both showed focal segmental glomerulosclerosis on renal biopsy. Of note, the father who was also homozygous for the mutation, had hypertension and mild proteinuria as a teen, but normal renal evaluation at age 46 years, suggesting the presence of modifying factors.
In affected members of 2 consanguineous families from Greece and Turkey, respectively, with NPHS3 (NPHS3; 610725), Boyer et al. (2010) identified a homozygous 3736C-T transition in exon 13 of the PLCE1 gene, resulting in an arg1246-to-ter (R1246X) substitution. Renal biopsies of these 3 patients showed focal segmental glomerulosclerosis. The same homozygous R1246X mutation was also found in 2 unrelated patients of Bosnian and Serbian descent with sporadic disease; renal biopsies in these patients showed diffuse mesangial sclerosis. Most patients had onset of nephrotic syndrome before age 1 year, and all had end-stage renal failure by age 7 years.
Boyer, O., Benoit, G., Gribouval, O., Nevo, F., Pawtowski, A., Bilge, I., Bircan, Z., Deschenes, G., Guay-Woodford, L. M., Hall, M., Macher, M.-A., Soulami, K., Stefanidis, C. J., Weiss, R., Loirat, C., Gubler, M.-C., Antignac, C. Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome. J. Med. Genet. 47: 445-452, 2010. [PubMed: 20591883] [Full Text: https://doi.org/10.1136/jmg.2009.076166]
Bunney, T. D., Harris, R., Lamuno Gandarillas, N., Josephs, M. B., Roe, S. M., Sorli, S. C., Paterson, H. F., Rodrigues-Lima, F., Esposito, D., Ponting, C. P., Gierschik, P., Pearl, L. H., Driscoll, P. C., Katan, M. Structural and mechanistic insights into Ras association domains of phospholipase C epsilon. Molec. Cell 21: 495-507, 2006. [PubMed: 16483931] [Full Text: https://doi.org/10.1016/j.molcel.2006.01.008]
Evellin, S., Nolte, J., Tysack, K., vom Dorp, F., Thiel, M., Oude Weernink, P. A., Jakobs, K. H., Webb, E. J., Lomasney, J. W., Schmidt, M. Stimulation of phospholipase C-epsilon by the M(3) muscarinic acetylcholine receptor mediated by cyclic AMP and the GTPase Rap2B. J. Biol. Chem. 277: 16805-16813, 2002. [PubMed: 11877431] [Full Text: https://doi.org/10.1074/jbc.M112024200]
Hinkes, B., Wiggins, R. C., Gbadegesin, R., Vlangos, C. N., Seelow, D., Nurnberg, G., Garg, P., Verma, R., Chaib, H., Hoskins, B. E., Ashraf, S., Becker, C., and 35 others. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nature Genet. 38: 1397-1405, 2006. [PubMed: 17086182] [Full Text: https://doi.org/10.1038/ng1918]
Lopez, I., Mak, E. C., Ding, J., Hamm, H. E., Lomasney, J. W. A novel bifunctional phospholipase C that is regulated by G-alpha(12) and stimulates the Ras/mitogen-activated protein kinase pathway. J. Biol. Chem. 276: 2758-2765, 2001. [PubMed: 11022047] [Full Text: https://doi.org/10.1074/jbc.M008119200]
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 143-150, 2000. [PubMed: 10819331] [Full Text: https://doi.org/10.1093/dnares/7.2.143]
Song, C., Hu, C.-D., Masago, M., Kariya, K., Yamawaki-Kataoka, Y., Shibatohge, M., Wu, D., Satoh, T., Kataoka, T. Regulation of a novel human phospholipase C, PLC-epsilon, through membrane targeting by Ras. J. Biol. Chem. 276: 2752-2757, 2001. [PubMed: 11022048] [Full Text: https://doi.org/10.1074/jbc.M008324200]
Song, C., Satoh, T., Edamatsu, H., Wu, D., Tadano, M., Gao, X., Kataoka, T. Differential roles of Ras and Rap1 in growth factor-dependent activation of phospholipase C-epsilon. Oncogene 21: 8105-8113, 2002. [PubMed: 12444546] [Full Text: https://doi.org/10.1038/sj.onc.1206003]