| First Author | Pokidysheva EN | Year | 2021 |
| Journal | J Biol Chem | Volume | 296 |
| Pages | 100590 | PubMed ID | 33774048 |
| Mgi Jnum | J:313275 | Mgi Id | MGI:6695625 |
| Doi | 10.1016/j.jbc.2021.100590 | Citation | Pokidysheva EN, et al. (2021) Collagen IV(alpha345) dysfunction in glomerular basement membrane diseases. I. Discovery of a COL4A3 variant in familial Goodpasture's and Alport diseases. J Biol Chem :100590 |
| abstractText | 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 IV(alpha345) 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 IV(alpha345) 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 alpha3 subunit of the alpha345 hexamer. A knock-in mouse harboring the variant displayed GBM abnormalities and proteinuria. This pathology phenocopied AS, which pinpointed the alpha345 hexamer as a focal point in GBM function and dysfunction. Crystallography and assembly studies revealed underlying hexamer mechanisms, as described in Companion Papers II and III. 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 alpha345 hexamer could therefore be a potential treatment for GBM diseases, and this knock-in mouse model is suitable for developing gene therapies. |
