title: Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 650-0017, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ohtsubo
authors.affiliation: Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, 658-0072, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Okada
authors.affiliation: 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.
authors.forename: Kandai
authors.initials: K
authors.lastname: Nozu
authors.affiliation: Division of Medical Informatics and Bioinformatics, Kobe University Hospital, Kobe, 658-0072, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takaoka
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 650-0017, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Shono
authors.affiliation: Medical Innovation Center, TMK project, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Asanuma
authors.affiliation: Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, 658-0072, Japan.
authors.forename: Lifang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Wakayama Medical University, Wakayama, 641-8509, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakanishi
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 650-0017, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Taniguchi-Ikeda
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 650-0017, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaito
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, 650-0017, Japan.
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, 658-0072, Japan.
authors.forename: Shun-Ichi
authors.initials: S
authors.lastname: Nakamura
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D016207:Cytokines / Q000235:genetics*; D005260:Female; D005353:Fibronectins; D015432:Glomerulonephritis, Membranoproliferative / Q000150:complications / Q000235:genetics*; D006493:Heparin; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: D016207:Cytokines; C067625:FN1 protein, human; D005353:Fibronectins; D006493:Heparin
keywords: Fibronectin; GFND; Heparin-binding domain; Integrin-binding domain; Nephropathy