FN1 gene encodes for the formation of fibronectin which is a glycoprotein of the extracellular matrix. It is essential to the formation of cartilaginous tissues and bones. Mutations in FN1 affect the cysteine residues that form disulfide bonds in the fibronectin type I domain responsible for the three-dimensional structure of the fibronectin. This leads to instability and risk of degradation by metalloproteases 9 and 13.
GDND2 is caused by mutations in the type-III domain in the C-terminal region. Mutations in this region cause decreased heparin and integrin binding, reduced endothelial cell spreading, and restriction in cytoskeletal reorganization. Glomerular selectivity and protein trafficking could be consequently affected. Variants in the III-2 domain reduce the secretion of the abnormal fibronectin which consequently accumulates within the cell. Accumulation in renal glomeruli cells is thought to be deleterious and the cause of GFND2. Mutations in FN1 will also have an impact on the formation of fibrils and will disturb the ratio of soluble and insoluble fibronectin. This abnormal fibronectin will affect the formation of the glomerular matrix.
GFND2 is inherited in an autosomal dominant manner.
FN1 GFND2