Identification of mutations in FN1 leading to glomerulopathy with fibronectin deposits
| Autor: | Hiroshi Kaito, Akemi Shono, Kazumoto Iijima, Taro Okada, Yutaka Takaoka, Lifang Zhang, Kandai Nozu, Shun-ichi Nakamura, Katsuhiko Asanuma, Mariko Taniguchi-Ikeda, Koichi Nakanishi, Hiromi Ohtsubo |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Adolescent Glomerulonephritis Membranoproliferative Integrin 030232 urology & nephrology medicine.disease_cause law.invention Pathogenesis 03 medical and health sciences 0302 clinical medicine Glomerulopathy law medicine Humans Child Aged Mutation biology Heparin business.industry Haplotype Autosomal dominant trait Middle Aged medicine.disease Molecular biology Fibronectins Fibronectin 030104 developmental biology Nephrology Pediatrics Perinatology and Child Health biology.protein Recombinant DNA Cytokines Kidney Failure Chronic Female business |
| Zdroj: | Pediatric Nephrology. 31:1459-1467 |
| ISSN: | 1432-198X 0931-041X |
| DOI: | 10.1007/s00467-016-3368-7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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