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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Acknowledgments
The results presented in this paper have not been published previously in whole or part, except in abstract format. This work was supported by a Grant-in-Aid for Young Scientists (B) (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (Subject ID: 24791062 to Hiromi Ohtsubo). We thank T. Kajimoto, S. Miya, C. Hirai, Y. Hashimura, T. Ninchoji, N. Morisada, S. Ishimori, F. Hashimoto, N. Matsunoshita, N. Kamyoshi, S. Minamikawa, and T. Yamamura for technical assistance and/or encouragement. Special thanks go to K. Jo, T. Okamoto, S. Sasaki, M. Fujieda, T. Kawanishi, T. Harada, A. Inaba, N. Miura, M. Toyoda, M. Nishida, H. Itoh, T. Udagawa, R. Katabuchi, N. Gotoh, O. Uchikoga, H. Fujii, K. Aramaki, S. Okuda, T. Kurosawa, K. Koike, Y. Hori, N. Uesugi, N. Miura, S. Isobe, K. Ishiyama, and S. Hirashio.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
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Informed consent was obtained from all individual participants included in the study.
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This study was supported by a Grant-in-Aid for Young Scientists (B) (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (Subject ID: 24791062 to Hiromi Ohtsubo).
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Hiromi Ohtsubo, Taro Okada and Kandai Nozu should be regarded as joint first authors.
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Ohtsubo, H., Okada, T., Nozu, K. et al. Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits. Pediatr Nephrol 31, 1459–1467 (2016). https://doi.org/10.1007/s00467-016-3368-7
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DOI: https://doi.org/10.1007/s00467-016-3368-7