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, for gaining better insights into the mechanisms leading to Alport syndrome and to the variability in the age of onset and associated phenotypes.

Anti–microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways

“…Expression of this mutation on a C57BL/6 background results in slower disease progression, and F1 progeny of this cross have intermediate disease progression (39). Dependence of the Alport syndrome phenotype disease progression on strain has also been observed in Col4a4 mutations (40). The efficacy described here is not limited to the 129X1/SvJ strain, as it has also been observed in the Col4A3 F1 progeny of 129X1/SvJ crossed with C57BL/6 mice (41).…”

X-Linked Alport Dogs Demonstrate Mesangial Filopodial Invasion of the Capillary Tuft as an Early Event in Glomerular Damage

“…[43] Even amongst the different mouse models of AS themselves, onset of proteinuria can vary. [11, 14, 15, 44, 45] Therefore, one must be cognizant of these variations when choosing a mouse model for therapeutic study. Our results show that the distinction of WT versus AS dogs based on proteinuria is evident even at earlier stages of disease, making it a better model to monitor response to therapy.…”

Translational value of animal models of kidney failure

“…Furthermore, heterozygous COL4A3 þ / À mice are a model of human thin membrane nephropathy developing hematuria, albuminuria and from age 12 months, renal failure (Beirowski et al, 2006). Recently, a spontaneous Col4a4 mutation was found to account for the bilateral wasting kidneys (bwk) phenotype in NONcNZO inbred mice characterized by albuminuria and progression to end-stage renal disease (Korstanje et al, 2014).…”