The PLCE1 gene is located on chromosome 10 at q23.3 and encodes the phospholipase C epsilon 1 protein, which is an enzyme that regulates proliferation, migration and differentiation of podocytes.
PLCE1 was first reported in relation to autosomal recessive nephrotic syndrome type 3 in 2006 (Hinkes et al., PMID: 10997929, OMIM:610725). The preferred disease name suggested for this disorder is ‘Nephrotic syndrome - PLCE1’. The mechanism of pathogenicity is known to be loss of function. Nephrotic syndrome - PLCE1 is characterized by significant protein loss in the urine within the first months of life causing generalized edema.
At least 46 variants (frameshift, nonsense, splice, missense) have been reported in 56 probands in 6 publications (PMIDs: 10997929, 35034193, 29127259, 25349199, 18709391, 18065803 included in this curation). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data.
This gene-disease association is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 25521631, 32238860, 32223311, 17942568, 10997929). PLCE1 knockout human podocytes showed reduced markers of podocytes including NPHS1, NEPH1, WT1, and SYPO (PMID: 32238860) in addition to reduced podocyte proliferation. Also, podocytes transfected with PLCE1 siRNA exhibited a significant decrease in Rac1 and Cdc42 levels that regulate podocyte actin cytoskeleton stabilization (PMID: 32238860). In particular, PLCE1 knockdown zebrafish showed signs of podocytopathy (PMID: 10997929). Interestingly, PLCE1 knockout mice exhibited normal kidney structure and function (PMIDs: 32223311, 10997929), however, a second hit such as hypertension (Angiotensin II treatment) or nephron loss (unilateral nephrectomy) caused the development of FSGS lesions (PMID: 32223311). A total of 5.5/6 pts. for experimental evidence was reached.
In summary, there is definitive evidence supporting the relationship between PLCE1 and autosomal recessive nephrotic syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
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