Absence of the alpha 6(IV) chain of collagen type IV in Alport syndrome isrelated to a failure at the protein assembly level and does not result in diffuse leiomyomatosis

X-linked Alport syndrome is a progressive nephropathy associated with mutat ions in the COL4A5 gene. The kidney usually lacks the alpha 3-alpha 6 chain s of collagen type IV, although each is coded by a separate gene. The molec ular basis for this loss remains unclear. In canine X-linked hereditary nep hritis, a model for X-linked Alport syndrome, a COL4A5 mutation results in reduced mRNA levels for the alpha 3, alpha 4, and alpha 5 chains in the kid ney, implying a mechanism coordinating the production of these 3 chains. To examine whether production of alpha 6 chain is under the same control, we studied smooth muscle cells from this animal model. We determined the canin e COL4A5 and COL4A6 genes are separated by 435 bp, with two first exons for COL4A6 separated by 978 bp, These two regions are greater than or equal to 78% identical to the human sequences that have promoter activity. Despite this potential basis for coordinated transcription of the COL4A5 and COL4A6 genes, the cub mRNA level remained normal in affected male dog smooth musc le while the alpha 5 mRNA level was markedly reduced. However, both alpha 5 and alpha 6 chains were absent at the protein level, Our results suggest t hat production of the alpha 6 chain is under a control mechanism separate f rom that coordinating the alpha 3-alpha 5 chains and that the lack of the a lpha 6 chain in Alport syndrome is related to a failure at the protein asse mbly level, raising the possibility that the alpha 5 and alpha 6 chains are present in the same network. The lack of the alpha 6 chain does not obviou sly result in disease, in particular leiomyomatosis, as is seen in Alport p atients with deletions involving the COL4A5 and COL4A6 genes.