Covered on Genetics Home Reference: congenital nephrotic syndromeFrom NCBI Gene: Nephrotic syndrome, type 3From UniProt: Nephrotic syndrome 3 (NPHS3): A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. Most patients with NPHS3 show diffuse mesangial sclerosis on renal biopsy, which is a pathologic entity characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen. [MIM:610725]

     From NCBI Gene: This gene encodes a phospholipase enzyme that catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate to generate two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). These second messengers subsequently regulate various processes affecting cell growth, differentiation, and gene expression. This enzyme is regulated by small monomeric GTPases of the Ras and Rho families and by heterotrimeric G proteins. In addition to its phospholipase C catalytic activity, this enzyme has an N-terminal domain with guanine nucleotide exchange (GEF) activity. Mutations in this gene cause early-onset nephrotic syndrome; characterized by proteinuria, edema, and diffuse mesangial sclerosis or focal and segmental glomerulosclerosis. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Sep 2009] From UniProt: The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. PLCE1 is a bifunctional enzyme which also regulates small GTPases of the Ras superfamily through its Ras guanine-exchange factor (RasGEF) activity. As an effector of heterotrimeric and small G-protein, it may play a role in cell survival, cell growth, actin organization and T-cell activation.

The following transcription factors affect gene expression:

• PPAR-gamma1
• PPAR-gamma2
• STAT3
• STAT5B
• GATA-1
• NF-1
• Bach1
• Lmo2

Tissue specificity:

Widely expressed. Isoform 1 is broadly expressed and only absent in peripheral blood leukocytes. Isoform 2 is specifically expressed in placenta, lung and spleen.

Induction:

Overexpressed during heart failure.

Enzyme Regulation:

Activated by the heterotrimeric G-protein subunits GNA12, GNA13 and GNB1-GNG2. Activated by HRAS, RAP1A, RHOA, RHOB, RHOC, RRAS and RRAS2. Activated by the G(s)-coupled GPCRs ADRB2, PTGER1 and CHRM3 through cyclic-AMP formation and RAP2B activation. Inhibited by G(i)-coupled GPCRs.

Molecular Function:

• Phosphatidylinositol Phospholipase C Activity
• Phospholipase C Activity
• Signal Transducer Activity, Downstream Of Receptor
• Guanyl-Nucleotide Exchange Factor Activity
• Ras Gtpase Binding
• Enzyme Binding
• Metal Ion Binding

Biological Processes:

• Activation Of Mapk Activity
• Regulation Of Cell Growth
• Phospholipid Metabolic Process
• Diacylglycerol Biosynthetic Process
• Regulation Of Smooth Muscle Contraction
• Cytoskeleton Organization
• Epidermal Growth Factor Receptor Signaling Pathway
• Phospholipase C-Activating G-Protein Coupled Receptor Signaling Pathway
• Positive Regulation Of Cytosolic Calcium Ion Concentration
• Protein Kinase C-Activating G-Protein Coupled Receptor Signaling Pathway
• Ras Protein Signal Transduction
• Heart Development
• Regulation Of G-Protein Coupled Receptor Protein Signaling Pathway
• Cell Proliferation
• Lipid Catabolic Process
• Calcium-Mediated Signaling
• Glomerulus Development
• Inositol Phosphate Metabolic Process
• Regulation Of Protein Kinase Activity
• Regulation Of Ras Protein Signal Transduction
• Inositol Phosphate-Mediated Signaling