Abstract
Alport syndrome is caused by mutations in the genes encoding α3, α4, or α5 (IV) chains. Unlike X-linked Alport mice, α5 and α6 (IV) chains are detected in the glomerular basement membrane of autosomal recessive Alport mice, however, the significance of this finding remains to be investigated. We therefore generated mice lacking both α3 and α6 (IV) chains and compared their renal function and survival with Col4a3 knockout mice of 129 × 1/Sv background. No significant difference was observed in the renal function or survival of the two groups, or when the mice were backcrossed once to C57BL/6 background. However, the survival of backcrossed double knockout mice was significantly longer than that of the mice of 129 × 1/Sv background, which suggests that other modifier genes were involved in this phenomenon. In further studies we identified two Alport patients who had a homozygous mutation in intron 46 of COL4A4. The α5 and α6 (IV) chains were focally detected in the glomerular basement membrane of these patients. These findings indicate that although α5 and α6 (IV) chains are induced in the glomerular basement membrane in autosomal recessive Alport syndrome, their induction does not seem to play a major compensatory role.
Highlights
Alport syndrome (AS), which is caused by mutations in either the COL4A3, COL4A4, or COL4A5 gene, is a progressive hereditary nephritic disease that leads to irreversible renal failure[5]
The blood urea nitrogen (BUN) levels of 3KO and DKO mice were significantly elevated in comparison to those of wild mice (WT) and Col4a6 −/−mice (6KO) at 11 weeks of age (#P < 0.05 versus WT, *P < 0.05 versus 6KO). (b) no significant differences were noted in the serum creatinine (Cr) levels of the 3KO and DKO mice from that of the WT mice, the Cr level of the 6KO mice was significantly lower than that of the WT mice at 7 weeks of age (**P < 0.05)
We demonstrated that there was no significant difference in the renal function or the survival between 3KO and DKO mice on the 129 × 1/Sv genetic background, a weak expression of the α5 and α6 (IV) chains in the GBM of 3KO mice was detected
Summary
Alport syndrome (AS), which is caused by mutations in either the COL4A3, COL4A4, or COL4A5 gene, is a progressive hereditary nephritic disease that leads to irreversible renal failure[5]. Autosomal recessive AS (ARAS), which is caused by a defective COL4A3 or COL4A4, accounts for approximately 15%8. In the GBMs of a canine model of ARAS20, and in Col4a3 −/−mice. In this latter study, affinity fractionation determined that the α5.α5.α6 (IV) isoform formed a network with the α1.α1.α2 isoform[21]. Affinity fractionation determined that the α5.α5.α6 (IV) isoform formed a network with the α1.α1.α2 isoform[21] It remains unknown whether the regulation of type IV collagen isoforms in humans differs from that in dogs or mice, since the presence of the α5 and α6 (IV) chains has not been clearly demonstrated in the GBM of ARAS patients. We investigated the role of the α5.α5.α6 (IV) isoform in the GBM on kidney function through the use of mice that lacked both the α3 and α6 (IV) chains
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