title: A mouse Col4a4 mutation causing Alport glomerulosclerosis with abnormal collagen α3α4α5(IV) trimers.
abstract: A spontaneous mutation termed bilateral wasting kidneys (bwk) was identified in a colony of NONcNZO recombinant inbred mice. These mice exhibit a rapid increase of urinary albumin at an early age associated with glomerulosclerosis, interstitial nephritis, and tubular atrophy. The mutation was mapped to a location on chromosome 1 containing the Col4a3 and Col4a4 genes, for which mutations in the human orthologs cause the hereditary nephritis Alport syndrome. DNA sequencing identified a G-to-A mutation in the conserved GT splice donor of Col4a4 intron 30, resulting in skipping of exon 30 but maintaining the mRNA reading frame. Protein analyses showed that mutant collagen α3α4α5(IV) trimers were secreted and incorporated into the glomerular basement membrane (GBM), but levels were low, and GBM lesions typical of Alport syndrome were observed. Moving the mutation into the more renal damage-prone DBA/2J and 129S1/SvImJ backgrounds revealed differences in albuminuria and its rate of increase, suggesting an interaction between the Col4a4 mutation and modifier genes. This novel mouse model of Alport syndrome is the only one shown to accumulate abnormal collagen α3α4α5(IV) in the GBM, as also found in a subset of Alport patients. These mice will be valuable for testing potential therapies, for understanding abnormal collagen IV structure and assembly, and for gaining better insights into the mechanisms leading to Alport syndrome, and to the variability in the age of onset and associated phenotypes.
authors: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors: Ron
authors: R
authors: Korstanje
authors: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors: Christina R
authors: CR
authors: Caputo
authors: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors: Rosalinda A
authors: RA
authors: Doty
authors: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors: Susan A
authors: SA
authors: Cook
authors: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors: Roderick T
authors: RT
authors: Bronson
authors: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors: Muriel T
authors: MT
authors: Davisson
authors: Renal Division, Washington University School of Medicine, St Louis, Missouri, USA.
authors: Jeffrey H
authors: JH
authors: Miner
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism*; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D050533:Glomerular Basement Membrane / Q000378:metabolism* / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D008811:Mice, Inbred DBA; D009154:Mutation; D009394:Nephritis, Hereditary / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D055503:Protein Multimerization; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D001324:Autoantigens; C549554:Col4a5 protein, mouse; D024141:Collagen Type IV; D012333:RNA, Messenger; C057112:type IV collagen alpha3 chain