AI Article Synopsis

  • Glomerulopathy with fibronectin deposits (GFND) is a rare genetic disorder leading to severe kidney issues due to excessive fibronectin buildup, with mutations usually found in the heparin-binding domains of the fibronectin 1 gene (FN1).
  • In a study involving 12 GFND families, researchers identified six FN1 mutations, five of which are novel, including one located in the integrin-binding domain, suggesting a broader genetic basis for the condition.
  • The novel mutation p.Pro1472del was associated with reduced cell binding capabilities, and the study highlights that patients typically show symptoms in early life, with some mutation carriers remaining asymptomatic, enhancing our understanding of GFND's mechanisms.

Article Abstract

Background: Glomerulopathy with fibronectin deposits (GFND) is a rare autosomal dominant disease characterized by massive fibronectin deposits, leading to end-stage renal failure. Although mutations within the heparin-binding domains of the fibronectin 1 gene (FN1) have been associated with GFND, no mutations have been reported within the integrin-binding domains.

Methods: In this study, FN1 mutational analysis was conducted in 12 families with GFND. Biochemical and functional features of mutated proteins were examined using recombinant fibronectin fragments encompassing both the integrin- and heparin-binding domains.

Results: We report six FN1 mutations from 12 families with GFND, including five that are novel (p.Pro969Leu, p.Pro1472del, p.Trp1925Cys, p.Lys1953_Ile1961del, and p.Leu1974Pro). p.Pro1472del is localized in the integrin-binding domain of fibronectin, while the others are in heparin-binding domains. We detected p.Tyr973Cys, p.Pro1472del, and p.Leu1974Pro mutations in multiple families, and haplotype analysis implied that p.Pro1472del and p.Leu1974Pro are founder mutations. The protein encoded by the novel integrin-binding domain mutation p.Pro1472del showed decreased cell binding ability via the integrin-binding site. Most affected patients developed urine abnormalities during the first or second decade of life, and some mutation carriers were completely asymptomatic.

Conclusions: This is the second large-scale analysis of GFND families and the first report of an integrin-binding domain mutation. These findings may help determine the pathogenesis of GFND.

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Source
http://dx.doi.org/10.1007/s00467-016-3368-7DOI Listing

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