Absence of the α6(IV) Chain of Collagen Type IV in Alport Syndrome Is Related to a Failure at the Protein Assembly Level and Does Not Result in Diffuse Leiomyomatosis

摘要

X-linked Alport syndrome is a progressive nephropathy associated with mutations in the COL4A5 gene. The kidney usually lacks the α3-α6 chains of collagen type IV, although each is coded by a separate gene. The molecular basis for this loss remains unclear. In canine X-linked hereditary nephritis, a model for X-linked Alport syndrome, a COL4A5 mutation results in reduced mRNA levels for the α3, α4, and α5 chains in the kidney, implying a mechanism coordinating the production of these 3 chains. To examine whether production of α6 chain is under the same control, we studied smooth muscle cells from this animal model. We determined the canine COL4A5 and COL4A6 genes are separated by 435 bp, with two first exons for COL4A6 separated by 978 bp. These two regions are ≥ 78% identical to the human sequences that have promoter activity. Despite this potential basis for coordinated transcription of the COL4A5 and COL4A6 genes, the α6 mRNA level remained normal in affected male dog smooth muscle while the α5 mRNA level was markedly reduced. However, both α5 and α6 chains were absent at the protein level. Our results suggest that production of the α6 chain is under a control mechanism separate from that coordinating the α3-α5 chains and that the lack of the α6 chain in Alport syndrome is related to a failure at the protein assembly level, raising the possibility that the α5 and α6 chains are present in the same network. The lack of the α6 chain does not obviously result in disease, in particular leiomyomatosis, as is seen in Alport patients with deletions involving the COL4A5 and COL4A6 genes.