| First Author | Odiatis C | Year | 2021 |
| Journal | Matrix Biol Plus | Volume | 9 |
| Pages | 100053 | PubMed ID | 33718859 |
| Mgi Jnum | J:330819 | Mgi Id | MGI:7333025 |
| Doi | 10.1016/j.mbplus.2020.100053 | Citation | Odiatis C, et al. (2021) A glycine substitution in the collagenous domain of Col4a3 in mice recapitulates late onset Alport syndrome. Matrix Biol Plus 9:100053 |
| abstractText | Alport syndrome (AS) is a severe inherited glomerulopathy caused by mutations in the genes encoding the alpha-chains of type-IV collagen, the most abundant component of the extracellular glomerular basement membrane (GBM). Currently most AS mouse models are knockout models for one of the collagen-IV genes. In contrast, about half of AS patients have missense mutations, with single aminoacid substitutions of glycine being the most common. The only mouse model for AS with a homozygous knockin missense mutation, Col4a3-p.Gly1332Glu, was partly described before by our group. Here, a detailed in-depth description of the same mouse is presented, along with another compound heterozygous mouse that carries the glycine substitution in trans with a knockout allele. Both mice recapitulate essential features of AS, including shorten lifespan by 30-35%, increased proteinuria, increased serum urea and creatinine, pathognomonic alternate GBM thinning and thickening, and podocyte foot process effacement. Notably, glomeruli and tubuli respond differently to mutant collagen-IV protomers, with reduced expression in tubules but apparently normal in glomeruli. However, equally important is the fact that in the glomeruli the mutant alpha3-chain as well as the normal alpha4/alpha5 chains seem to undergo a cleavage at, or near the point of the mutation, possibly by the metalloproteinase MMP-9, producing a 35kDa C-terminal fragment. These mouse models represent a good tool for better understanding the spectrum of molecular mechanisms governing collagen-IV nephropathies and could be used for pre-clinical studies aimed at better treatments for AS. |
