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 Ikeda, Hiroshi Kaito, Kazumoto Iijima, Shun ichi Nakamura

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1459-1467
Number of pages9
JournalPediatric Nephrology
Volume31
Issue number9
DOIs
Publication statusPublished - 01-09-2016

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Fibronectins
Integrins
Mutation
Genes
Heparin
Aptitude
Glomerulopathy with fibronectin deposits
Haplotypes
Chronic Kidney Failure
Proteins
Binding Sites
Urine

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Nephrology

Cite this

Ohtsubo, H., Okada, T., Nozu, K., Takaoka, Y., Shono, A., Asanuma, 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
Ohtsubo, Hiromi ; Okada, Taro ; Nozu, Kandai ; Takaoka, Yutaka ; Shono, Akemi ; Asanuma, Katsuhiko ; Zhang, Lifang ; Nakanishi, Koichi ; Ikeda, Mariko ; Kaito, Hiroshi ; Iijima, Kazumoto ; Nakamura, Shun ichi. / Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits. In: Pediatric Nephrology. 2016 ; Vol. 31, No. 9. pp. 1459-1467.
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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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Ohtsubo, H, Okada, T, Nozu, K, Takaoka, Y, Shono, A, Asanuma, K, Zhang, L, Nakanishi, K, Ikeda, M, Kaito, H, Iijima, K & Nakamura, SI 2016, 'Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits', Pediatric Nephrology, vol. 31, no. 9, pp. 1459-1467. https://doi.org/10.1007/s00467-016-3368-7

Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits. / Ohtsubo, Hiromi; Okada, Taro; Nozu, Kandai; Takaoka, Yutaka; Shono, Akemi; Asanuma, Katsuhiko; Zhang, Lifang; Nakanishi, Koichi; Ikeda, Mariko; Kaito, Hiroshi; Iijima, Kazumoto; Nakamura, Shun ichi.

In: Pediatric Nephrology, Vol. 31, No. 9, 01.09.2016, p. 1459-1467.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits

AU - Ohtsubo, Hiromi

AU - Okada, Taro

AU - Nozu, Kandai

AU - Takaoka, Yutaka

AU - Shono, Akemi

AU - Asanuma, Katsuhiko

AU - Zhang, Lifang

AU - Nakanishi, Koichi

AU - Ikeda, Mariko

AU - Kaito, Hiroshi

AU - Iijima, Kazumoto

AU - Nakamura, Shun ichi

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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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