A glycine substitution in the collagenous domain of Col4a3 in mice recapitulates late onset Alport syndrome.

Autor:	Odiatis C; Center of Excellence in Biobanking and Biomedical Research, Molecular Medicine Research Center, University of Cyprus Medical School, Cyprus., Savva I; Center of Excellence in Biobanking and Biomedical Research, Molecular Medicine Research Center, University of Cyprus Medical School, Cyprus., Pieri M; Department of Life and Health Sciences, School of Sciences and Engineering, University of Nicosia, Cyprus., Ioannou P; Center of Excellence in Biobanking and Biomedical Research, Molecular Medicine Research Center, University of Cyprus Medical School, Cyprus., Petrou P; Department of Biochemistry, The Cyprus Institute of Neurology and Genetics, Cyprus., Papagregoriou G; Center of Excellence in Biobanking and Biomedical Research, Molecular Medicine Research Center, University of Cyprus Medical School, Cyprus., Antoniadou K; Center of Excellence in Biobanking and Biomedical Research, Molecular Medicine Research Center, University of Cyprus Medical School, Cyprus., Makrides N; Department of Developmental Functional Genetics, The Cyprus Institute of Neurology and Genetics, Cyprus., Stefanou C; Center of Excellence in Biobanking and Biomedical Research, Molecular Medicine Research Center, University of Cyprus Medical School, Cyprus., Ljubanović DG; Department for Nephropathology and Electron microscopy, University of Zagreb, Croatia., Nikolaou G; Veterinary diagnostic laboratory, Vet ex Machina LTD, Nicosia, Cyprus., Borza DB; Dept. of Microbiology, Immunology and Physiology, Meharry Medical College, Nashville, TN, United States of America., Stylianou K; Department of Nephrology, University of Crete Medical School, Greece., Gross O; Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany., Deltas C; Center of Excellence in Biobanking and Biomedical Research, Molecular Medicine Research Center, University of Cyprus Medical School, Cyprus.
Jazyk:	angličtina
Zdroj:	Matrix biology plus [Matrix Biol Plus] 2020 Dec 30; Vol. 9, pp. 100053. Date of Electronic Publication: 2020 Dec 30 (Print Publication: 2021).
DOI:	10.1016/j.mbplus.2020.100053
Abstrakt:	Alport syndrome (AS) is a severe inherited glomerulopathy caused by mutations in the genes encoding the α-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 α3-chain as well as the normal α4/α5 chains seem to undergo a cleavage at, or near the point of the mutation, possibly by the metalloproteinase MMP-9, producing a 35 kDa 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. (© 2021 The Authors.)
Databáze:	MEDLINE
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