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PLCE1
phospholipase C epsilon 1
PLCE1 is located on the long (q) arm of chromosome 10, at band 10q23.33. Arm ratio per GRCh38 - banding schematic.
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Overview
The PLCE1 gene encodes phospholipase C epsilon 1, a member of the phospholipase C enzyme family responsible for cleaving specific membrane phospholipids. This enzyme plays a crucial role in cellular signalling cascades that coordinate diverse processes including cell growth, differentiation, and tissue architecture during development. Pathogenic variants in PLCE1 are inherited in an autosomal recessive pattern, meaning affected individuals carry two altered copies of the gene. Loss of functional enzyme activity particularly impacts kidney filtration barriers, resulting in early-onset proteinuric renal disease. The gene is included on NHS carrier screening panels due to the severe nature of associated conditions and the availability of genetic testing through UK clinical pathways.
What the gene does
Phospholipase C epsilon 1 functions as a lipid-modifying enzyme that catalyses the hydrolysis of phosphatidylinositol 4,5-bisphosphate into two second messengers: inositol 1,4,5-trisphosphate and diacylglycerol. These molecules trigger downstream signalling events including calcium release from intracellular stores and activation of protein kinase C. The enzyme integrates signals from both small GTPases of the Ras and Rho families and heterotrimeric G proteins, positioning it at a critical node in cellular communication networks. Within the kidney, PLCE1 is essential for maintaining the specialised structure of podocytes, the epithelial cells that form the filtration barrier in glomeruli. The enzyme's activity coordinates cytoskeletal organisation and cell-cell adhesion processes required for normal podocyte foot process architecture. Disruption of these signalling pathways leads to structural defects in the glomerular filtration barrier, permitting inappropriate protein loss into urine.
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Chromosome location
PLCE1 is located on chromosome 10 at band q23.33, a region on the long arm of chromosome 10. The gene spans a substantial genomic interval and encodes a large multi-domain protein. This chromosomal location places PLCE1 within a region that has been associated with various genetic disorders affecting multiple organ systems.
Protein structure
The PLCE1 protein comprises 2302 amino acids organised into multiple functional domains that confer its dual roles as both a lipase and a signalling scaffold. The Ras-GEF domain (amino acids 531-790) enables the protein to activate small GTPases, linking phospholipase activity to Ras-family signalling pathways. Two catalytic domains essential for lipase function are positioned in the C-terminal half: the PI-PLC X-box domain (amino acids 1392-1540) and PI-PLC Y-box domain (amino acids 1730-1846) together form the active site that cleaves phosphoinositide substrates. A region spanning amino acids 1686-1764 is required for activation by RHOA, RHOB, GNA12, GNA13 and G-beta gamma, allowing the enzyme to respond to multiple upstream signals. The C2 domain (amino acids 1851-1976) mediates calcium-dependent membrane binding. Two Ras-associating domains (amino acids 2012-2114 and 2135-2238) enable direct interaction with activated Ras proteins. Several disordered regions are interspersed throughout the sequence, likely providing flexibility for conformational changes during catalysis and protein-protein interactions.
Key variants
Pathogenic variants in PLCE1 typically result in loss of enzyme function through mechanisms including premature termination, frameshift alterations, or missense changes that disrupt catalytic activity or protein stability. The autosomal recessive inheritance pattern means individuals must inherit altered copies from both parents to develop clinical manifestations. Carriers with a single pathogenic variant generally remain asymptomatic. The variant spectrum includes truncating mutations that eliminate critical catalytic domains as well as missense variants affecting residues essential for substrate binding or enzymatic turnover.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1477C>T | p.Arg493Ter | Pathogenic | ★★☆☆ | Nephrotic syndrome, type 3 |
c.3058C>T | p.Gln1020Ter | Pathogenic | ★★☆☆ | Nephrotic syndrome, type 3 |
c.3338_3339del | p.Lys1113fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nephrotic syndrome, type 3 |
c.3736C>T | p.Arg1246Ter | Pathogenic | ★★☆☆ | Nephrotic syndrome, type 3 |
c.4192dup | p.Leu1398fs | Pathogenic | ★★☆☆ | Nephrotic syndrome, type 3 |
c.4483C>T | p.Arg1495Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Nephrotic syndrome, type 3 |
c.5979del | p.Gly1994fs | Pathogenic | ★★☆☆ | Nephrotic syndrome, type 3 |
c.961C>T | p.Arg321Ter | Pathogenic | ★★☆☆ | Nephrotic syndrome, type 3 |
c.5881C>T | p.Arg1961Ter | Pathogenic | ★☆☆☆ | not provided |
c.789C>A | p.Tyr263Ter | Pathogenic | ★☆☆☆ | Nephrotic syndrome, type 3 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in PLCE1 cause early-onset nephrotic syndrome, characterised by massive proteinuria, hypoalbuminaemia, and oedema due to glomerular filtration barrier dysfunction. Affected individuals typically present in infancy or early childhood with progressive renal impairment that often advances to end-stage kidney disease requiring dialysis or transplantation. Some patients exhibit additional features including neurological involvement. The severity and age of onset can vary depending on the specific variants inherited and residual enzyme activity.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PLCE1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
PLCE1 is designated a green gene on multiple NHS Genomic Medicine Service PanelApp panels, indicating strong evidence supporting its role in human disease. The gene appears on the DDG2P panel, the Proteinuric renal disease panel (R195), and the Unexplained kidney failure in young people panel. This classification reflects consensus among UK clinical genetics experts that PLCE1 variants cause inherited kidney disease with sufficient evidence for diagnostic and carrier testing through NHS laboratories. Genetic testing for PLCE1 variants may be offered to individuals with unexplained early-onset nephrotic syndrome or family history suggestive of autosomal recessive renal disease.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of a PLCE1 variant?
A carrier has one pathogenic variant and one working copy of PLCE1. Carriers typically have no symptoms because the functional copy provides sufficient enzyme activity. However, if both parents are carriers, each pregnancy has a 25% chance of inheriting two pathogenic variants and developing nephrotic syndrome.
How is PLCE1-related nephrotic syndrome diagnosed?
Diagnosis combines clinical findings of proteinuria and kidney dysfunction with genetic testing to identify biallelic pathogenic variants in PLCE1. Kidney biopsy may show characteristic podocyte structural abnormalities. Genetic confirmation guides management and enables family screening.
Is PLCE1 included in UK carrier screening programmes?
PLCE1 is included on autosomal recessive carrier screening panels used in the UK, particularly for individuals with family history of early-onset kidney disease or consanguineous relationships. Testing is available through NHS genetics services and private providers offering comprehensive carrier screening.