@article{Pokidysheva:2021:10.1016/j.jbc.2021.100590,
author = {Pokidysheva, EN and Seeger, H and Pedchenko, V and Chetyrkin, S and Bergmann, C and Abrahamson, D and Cui, ZW and Delpire, E and Fervenza, F and Fidler, AL and Fogo, AB and Gaspert, A and Grohmann, M and Gross, O and Haddad, G and Harris, RC and Kashtan, C and Kitching, AR and Lorenzen, JM and McAdoo, S and Pusey, CD and Segelmark, M and Simmons, A and Voziyan, PA and Wagner, T and Wüthrich, RP and Zhao, M-H and Boudko, SP and Kistler, AD and Hudson, BG},
doi = {10.1016/j.jbc.2021.100590},
journal = {Journal of Biological Chemistry},
title = {Collagen IVα345 dysfunction in glomerular basement membrane diseases. I. Discovery of a COL4A3 variant in familial Goodpasture's and Alport diseases},
url = {http://dx.doi.org/10.1016/j.jbc.2021.100590},
volume = {296},
year = {2021}
}

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TY  - JOUR
AB  - 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 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 α345 hexamer could therefore be a potential treatment for GBM diseases, and this knock-in mouse model is suitable for developing gene therapies.
AU  - Pokidysheva,EN
AU  - Seeger,H
AU  - Pedchenko,V
AU  - Chetyrkin,S
AU  - Bergmann,C
AU  - Abrahamson,D
AU  - Cui,ZW
AU  - Delpire,E
AU  - Fervenza,F
AU  - Fidler,AL
AU  - Fogo,AB
AU  - Gaspert,A
AU  - Grohmann,M
AU  - Gross,O
AU  - Haddad,G
AU  - Harris,RC
AU  - Kashtan,C
AU  - Kitching,AR
AU  - Lorenzen,JM
AU  - McAdoo,S
AU  - Pusey,CD
AU  - Segelmark,M
AU  - Simmons,A
AU  - Voziyan,PA
AU  - Wagner,T
AU  - Wüthrich,RP
AU  - Zhao,M-H
AU  - Boudko,SP
AU  - Kistler,AD
AU  - Hudson,BG
DO  - 10.1016/j.jbc.2021.100590
PY  - 2021///
SN  - 0021-9258
TI  - Collagen IVα345 dysfunction in glomerular basement membrane diseases. I. Discovery of a COL4A3 variant in familial Goodpasture's and Alport diseases
T2  - Journal of Biological Chemistry
UR  - http://dx.doi.org/10.1016/j.jbc.2021.100590
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33774048
UR  - http://hdl.handle.net/10044/1/89341
VL  - 296
ER  - 

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