Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits

Hiromi Ohtsubo, Taro Okada, Kandai Nozu, Yutaka Takaoka, Akemi Shono, Katsuhiko Asanuma, Lifang Zhang, Koichi Nakanishi, Mariko Taniguchi-Ikeda, Hiroshi Kaito, Kazumoto Iijima, Shun ichi Nakamura

研究成果: Article

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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.

元の言語English
ページ(範囲)1459-1467
ページ数9
ジャーナルPediatric Nephrology
31
発行部数9
DOI
出版物ステータスPublished - 01-09-2016

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All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Nephrology

これを引用

Ohtsubo, H., Okada, T., Nozu, K., Takaoka, Y., Shono, A., Asanuma, K., Zhang, L., Nakanishi, K., Taniguchi-Ikeda, M., Kaito, H., Iijima, K., & Nakamura, S. I. (2016). Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits. Pediatric Nephrology, 31(9), 1459-1467. https://doi.org/10.1007/s00467-016-3368-7