Hiromi Ohtsubo1, Taro Okada2, Kandai Nozu3, Yutaka Takaoka4, Akemi Shono1, Katsuhiko Asanuma5, Lifang Zhang2, Koichi Nakanishi6, Mariko Taniguchi-Ikeda1, Hiroshi Kaito1, Kazumoto Iijima1, Shun-Ichi Nakamura2. 1. Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 650-0017, Japan. 2. Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, 658-0072, Japan. 3. Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 650-0017, Japan. nozu@med.kobe-u.ac.jp. 4. Division of Medical Informatics and Bioinformatics, Kobe University Hospital, Kobe, 658-0072, Japan. 5. Medical Innovation Center, TMK project, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan. 6. Department of Pediatrics, Wakayama Medical University, Wakayama, 641-8509, Japan.
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.
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.
Authors: T E Petersen; H C Thøgersen; K Skorstengaard; K Vibe-Pedersen; P Sahl; L Sottrup-Jensen; S Magnusson Journal: Proc Natl Acad Sci U S A Date: 1983-01 Impact factor: 11.205
Authors: Chae Syng Lee; He Fu; Nissan Baratang; Justine Rousseau; Heena Kumra; V Reid Sutton; Marcello Niceta; Andrea Ciolfi; Guilherme Yamamoto; Débora Bertola; Carlo L Marcelis; Dorien Lugtenberg; Andrea Bartuli; Choel Kim; Julie Hoover-Fong; Nara Sobreira; Richard Pauli; Carlos Bacino; Deborah Krakow; Jillian Parboosingh; Patrick Yap; Ariana Kariminejad; Marie T McDonald; Mariana I Aracena; Ekkehart Lausch; Sheila Unger; Andrea Superti-Furga; James T Lu; Dan H Cohn; Marco Tartaglia; Brendan H Lee; Dieter P Reinhardt; Philippe M Campeau Journal: Am J Hum Genet Date: 2017-11-02 Impact factor: 11.025