fibronectin glomerulopathy At least three mutations in the FN1 gene have been found to cause fibronectin glomerulopathy, a progressive kidney disease that usually begins in adulthood and results in irreversible kidney failure (end-stage renal disease). FN1 gene mutations account for about 40 percent of cases of fibronectin glomerulopathy. The FN1 gene mutations change single protein building blocks (amino acids) in the fibronectin-1 protein. One mutation that occurs in multiple families replaces the amino acid tyrosine with the amino acid cysteine at position 973 in the fibronectin-1 protein (written as Tyr973Cys or Y973C). FN1 gene mutations impair the protein's ability to bind to cells and proteins. The unbound fibronectin-1 protein, specifically soluble plasma fibronectin-1, is deposited in the glomeruli of the kidneys. These structures are clusters of tiny blood vessels in the kidneys that filter waste products from blood, which are then released in urine. Even though there is an abundance of fibronectin-1 in the glomeruli, the extracellular matrix that supports the blood vessels is weak because the altered fibronectin-1 cannot assist in the matrix's continual formation. Without a strong cellular support network, the glomeruli are less able to filter waste. As a result, products that normally are retained by the body, such as protein and blood, get released in the urine, and acids are not properly filtered from the blood. Over time, the kidneys' ability to filter waste decreases until the kidneys can no longer function, resulting in end-stage renal disease.

     The FN1 gene provides instructions for making two types of the fibronectin-1 protein: soluble plasma fibronectin-1 and insoluble cellular fibronectin-1. Liver cells produce soluble plasma fibronectin-1 and release it into the bloodstream, where it is mainly involved in blood clotting and wound healing. Soluble plasma fibronectin-1 functions outside of cells (in the extracellular spaces), attaching (binding) to the surface of cells and binding to proteins, including other fibronectin-1 proteins. The attachment of these proteins form fibers that assist with tissue repair after an injury. Fibronectin-1 binding also helps with the continual formation of the extracellular matrix, which is an intricate lattice of proteins and other molecules that is made in the spaces between cells. This matrix provides structure and strength to tissues that support the body's organs. Many other cell types produce insoluble cellular fibronectin-1, which is released into the extracellular space and contributes to the creation of fibers and extracellular matrix. Both types of fibronectin-1 help individual cells expand (spread) and move (migrate) to cover more space and also influence cell shape and maturation (differentiation).

The following transcription factors affect gene expression:

• NF-kappaB
• CREB
• AP-1
• c-Jun
• deltaCREB
• STAT3
• NF-kappaB1
• Sp1
• c-Fos

Tissue specificity:

Plasma FN (soluble dimeric form) is secreted by hepatocytes. Cellular FN (dimeric or cross-linked multimeric forms), made by fibroblasts, epithelial and other cell types, is deposited as fibrils in the extracellular matrix. Ugl-Y1, Ugl-Y2 and Ugl-Y3 are found in urine.

Developmental stage:

Ugl-Y1, Ugl-Y2 and Ugl-Y3 are present in the urine from 0 to 17 years of age.

Molecular Function:

• Protease Binding
• Integrin Binding
• Collagen Binding
• Heparin Binding
• Peptidase Activator Activity
• Identical Protein Binding
• Mercury Ion Binding

Biological Processes:

• Angiogenesis
• Cell Activation
• Regulation Of Protein Phosphorylation
• Platelet Degranulation
• Response To Ischemia
• Acute-Phase Response
• Cell-Substrate Junction Assembly
• Cell Adhesion
• Calcium-Independent Cell-Matrix Adhesion
• Positive Regulation Of Cell Proliferation
• Glial Cell Migration
• Regulation Of Cell Shape
• Response To Wounding
• Response To Ozone
• Positive Regulation Of Gene Expression
• Peptide Cross-Linking
• Extracellular Matrix Disassembly
• Extracellular Matrix Organization
• Integrin Activation
• Substrate Adhesion-Dependent Cell Spreading
• Cellular Response To Vascular Endothelial Growth Factor Stimulus
• Endodermal Cell Differentiation
• Cellular Response To Platelet-Derived Growth Factor Stimulus
• Wound Healing
• Negative Regulation Of Apoptotic Process
• Positive Regulation Of Axon Extension
• Positive Regulation Of Fibroblast Proliferation
• Leukocyte Migration
• Positive Regulation Of Chemotaxis
• Response To Glucocorticoid
• Regulation Of Erk1 And Erk2 Cascade
• Cellular Response To Lipopolysaccharide
• Cellular Response To Mercury Ion
• Cellular Response To Glucose Stimulus
• Cellular Response To Interleukin-1
• Cellular Response To Prostaglandin E Stimulus
• Cellular Response To Transforming Growth Factor Beta Stimulus
• Cellular Response To Bmp Stimulus
• Positive Regulation Of Substrate-Dependent Cell Migration, Cell Attachment To Substrate
• Negative Regulation Of Transforming Growth Factor-Beta Secretion

Drug Bank:

• Ocriplasmin