Mutations in FN are associated with glomerulopathy, but when we studied mutant proteins, the single-nucleotide mutations had only minor effects on conformation and matrix assembly.
These data, together with a recent report associating mutations in the FN gene to a form of glomerulopathy, clearly show that mutations in constitutive exons or misregulation of alternatively spliced domains of the FN gene may have nonlethal pathological consequences.
Glomerulopathy with fibronectin (FN) deposits (GFND) is an autosomal dominant disease with age-related penetrance, characterized by proteinuria, microscopic hematuria, hypertension, and massive glomerular deposits of FN that lead to end-stage renal failure.
Thus, UG is essential for maintaining normal renal function in mice, which raises the possibility that an analogous pathogenic mechanism may underlie genetic Fn-deposit human glomerular disease.
Glomeruli from humans with diabetic nephropathy also showed a striking increase in immunoreactive TGF-beta protein and deposition of the special form of fibronectin, whereas glomeruli from normal subjects or from individuals with other glomerular diseases (where extracellular matrix accumulation is not a feature) were negative or barely positive.