Mutations in FN1 cause glomerulopathy with fibronectin deposits

doi:10.1073/pnas.0707730105

Mutations in FN1 cause glomerulopathy with fibronectin deposits

*Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Villa Camozzi, Ranica, Bergamo 24020, Italy;
^†Departments of Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, MI 48109;
^‡Department of Infection Biology, Leibniz Institute for Natural Products Research and Infection Biology, Hans Knoell Institute D-07745, Jena, Germany;
^§University of Siena Policlinico Le Scotte, Siena 53100, Italy; and
^¶Department of Nephrology and Dialysis, Azienda Ospedaliera, Ospedali Riuniti di Bergamo 24128, Italy

Edited by Richard P. Lifton, Yale University School of Medicine, New Haven, CT, and approved December 26, 2007 (received for review August 16, 2007)

Abstract

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. The genetic abnormality underlying GFND was still unknown. We hypothesized that mutations in FN1, which encodes FN, were the cause of GFND. In a large Italian pedigree with eight affected subjects, we found linkage with GFND at the FN1 locus at 2q32. We sequenced the FN1 in 15 unrelated pedigrees and found three heterozygous missense mutations, the W1925R, L1974R, and Y973C, that cosegregated with the disease in six pedigrees. The mutations affected two domains of FN (Hep-II domain for the W1925R and the L1974R, and Hep-III domain for the Y973C) that play key roles in FN–cell interaction and in FN fibrillogenesis. Mutant recombinant Hep-II fragments were expressed, and functional studies revealed a lower binding to heparin and to endothelial cells and podocytes compared with wild-type Hep-II and an impaired capability to induce endothelial cell spreading and cytoskeletal reorganization. Overall dominant mutations in FN1 accounted for 40% of cases of GFND in our study group. These findings may help understanding the pathogenesis of proteinuria and glomerular FN deposits in GFND and possibly in more common renal diseases such as diabetic nephropathy, IgA nephropathy, and lupus nephritis. To our knowledge no FN1 mutation causing a human disease was previously reported.

Footnotes

^‖To whom correspondence should be addressed. E-mail: gremuzzi{at}marionegri.it
Author contributions: G.R. and M.N. designed research; F.C., R.D., F.B., F.H., P.F.Z., E.B., E.O., M.T., M.R.C., and R.A. performed research; F.H. contributed new reagents/analytic tools; R.D., F.H., C.S., A.R., J.C., G.R., and M.N. analyzed data; and F.C. and M.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0707730105/DC1.