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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http://dx.doi.org/10.1007/s00467-016-3368-7 | DOI Listing |
Mol Med
January 2025
Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY, USA.
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February 2025
Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. Electronic address:
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School of Basic Medicine, Gannan Medical University, Ganzhou, China.
Extracellular Ca is the first ligand that has been confirmed to function by activating the calcium-sensing receptor (CaSR), a member of G-protein coupled receptors. CaSR controls not only calcium homeostasis, but also plays a pivotal role in many cellular processes such as cell proliferation and apoptosis; moreover, it is implicated in the development of cardiovascular diseases. TGF-β/Smads signaling pathway is a classical pathway of renal fibrosis.
View Article and Find Full Text PDFMedicina (Kaunas)
December 2024
Department of Otolaryngology-Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
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November 2024
Regenerative, Modular & Developmental Engineering Laboratory (REMODEL) and Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences Building, University of Galway, H91 TK33 Galway, Ireland.
Despite the promising potential of cell-based therapies developed using tissue engineering techniques to treat a wide range of diseases, including limbal stem cell deficiency (LSCD), which leads to corneal blindness, their commercialization remains constrained. This is primarily attributable to the limited cell sources, the use of non-standardizable, unscalable, and unsustainable techniques, and the extended manufacturing processes required to produce transplantable tissue-like surrogates. Herein, we present the first demonstration of the potential of a novel approach combining collagen films (CF), hyaluronic acid (HA), human telomerase-immortalized limbal epithelial stem cells (T-LESCs), and macromolecular crowding (MMC) to develop innovative biomimetic substrates for limbal epithelial stem cells (LESCs).
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