Collagen IVα345 dysfunction in glomerular basement membrane diseases. I. Discovery of a COL4A3 variant in familial Goodpasture’s and Alport diseases
| Autor: | George Haddad, Charles D. Pusey, Agnes B. Fogo, Dale R. Abrahamson, Rudolf P. Wüthrich, Clifford E. Kashtan, Alicia Simmons, Paul A. Voziyan, Fernando C. Fervenza, Sergei P. Boudko, Timo Wagner, Zhao Wei Cui, A. Richard Kitching, Raymond C. Harris, Eric Delpire, Andreas D. Kistler, Johan M. Lorenzen, Ming-Hui Zhao, Aaron L. Fidler, Sergei V. Chetyrkin, Ariana Gaspert, Carsten Bergmann, Oliver Gross, Billy G. Hudson, Maik Grohmann, Marten Segelmark, Harald Seeger, Elena Pokidysheva, Stephen P. McAdoo, Vadim Pedchenko |
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| Rok vydání: | 2021 |
| Předmět: |
collagen
Models Molecular 0301 basic medicine Anti-Glomerular Basement Membrane Disease Genetic enhancement Nephritis Hereditary Random hexamer urologic and male genital diseases Biochemistry Extracellular matrix Diabetic nephropathy Mice Medicine Goodpasture syndrome 11 Medical and Health Sciences Glomerular basement membrane Editors' Pick medicine.anatomical_structure AS Alport syndrome 03 Chemical Sciences GBM glomerular basement membrane Research Article Signal Transduction Collagen Type IV Biochemistry & Molecular Biology GP Goodpasture’s disease extracellular matrix DN diabetic nephropathy 03 medical and health sciences genetic disease Animals Alport syndrome Protein Structure Quaternary Molecular Biology Basement membrane 030102 biochemistry & molecular biology urogenital system business.industry diabetic nephropathy animal model Cell Biology 06 Biological Sciences medicine.disease 030104 developmental biology BM basement membrane Mutation Cancer research PTM posttranslational modification Protein Multimerization business |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | Diseases of the glomerular basement membrane (GBM), such as Goodpasture’s disease (GP) and Alport syndrome (AS), are a major cause of chronic kidney failure and an unmet medical need. Collagen IVα345 is an important architectural element of the GBM that was discovered in previous research on GP and AS. How this collagen enables GBM to function as a permselective filter and how structural defects cause renal failure remain an enigma. We found a distinctive genetic variant of collagen IVα345 in both a familial GP case and four AS kindreds that provided insights into these mechanisms. The variant is an 8-residue appendage at the C-terminus of the α3 subunit of the α345 hexamer. A knock-in mouse harboring the variant displayed GBM abnormalities and proteinuria. This pathology phenocopied AS, which pinpointed the α345 hexamer as a focal point in GBM function and dysfunction. Crystallography and assembly studies revealed underlying hexamer mechanisms, as described in Boudko et al. and Pedchenko et al. Bioactive sites on the hexamer surface were identified where pathogenic pathways of GP and AS converge and, potentially, that of diabetic nephropathy (DN). We conclude that the hexamer functions include signaling and organizing macromolecular complexes, which enable GBM assembly and function. Therapeutic modulation or replacement of α345 hexamer could therefore be a potential treatment for GBM diseases, and this knock-in mouse model is suitable for developing gene therapies. |
| Databáze: | OpenAIRE |
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