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Mutations in FN1 cause glomerulopathy with fibronectin deposits
Federica Castelletti1, Roberta Donadelli, Federica Banterla
1Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Villa Camozzi, Ranica, Bergamo 24020, Italy.
Summary
Genetic mutations in the fibronectin 1 (FN1) gene cause a rare kidney disease called glomerulopathy with fibronectin deposits (GFND). These FN1 mutations lead to massive fibronectin deposits in the glomerulus, causing end-stage renal failure.
Area of Science:
- Nephrology
- Genetics
- Molecular Biology
Background:
- Glomerulopathy with fibronectin deposits (GFND) is an autosomal dominant kidney disease.
- GFND is characterized by proteinuria, hematuria, hypertension, and progressive renal failure due to massive glomerular fibronectin deposits.
- The genetic cause of GFND remained unknown.
Purpose of the Study:
- To identify the genetic basis of GFND.
- To investigate the role of fibronectin 1 (FN1) gene mutations in GFND pathogenesis.
Main Methods:
- Linkage analysis in a large Italian pedigree identified the FN1 locus.
- FN1 gene sequencing in 15 unrelated pedigrees revealed heterozygous missense mutations (W1925R, L1974R, Y973C).
- Functional studies of mutant recombinant fibronectin (FN) fragments assessed heparin and cell binding, and cell spreading capabilities.
Main Results:
- Three heterozygous missense mutations in FN1 (W1925R, L1974R, Y973C) were identified and cosegregated with GFND in affected families.
- Mutations affected critical FN domains (Hep-II and Hep-III), impairing heparin and cell (endothelial cells, podocytes) binding, and endothelial cell spreading.
- Dominant FN1 mutations accounted for 40% of GFND cases in the study cohort.
Conclusions:
- Mutations in the FN1 gene are a cause of GFND.
- Altered fibronectin function due to these mutations contributes to glomerular fibronectin deposition and renal failure.
- Findings provide insights into GFND pathogenesis and may inform understanding of other proteinuric kidney diseases.
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