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(American Journal of Pathology. 1999;154:1883-1891.)
© 1999 American Society for Investigative Pathology

Regular Articles

Absence of the 6(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

Keqin Zheng^*, Scott Harvey^*, Yoshikazu Sado, Ichiro Naito, Yoshifumi Ninomiya^§, Robert Jacobs^¶ and Paul S. Thorner^*

From the Division of Pathology,^*
Hospital for Sick Children and University of Toronto, Toronto, Canada; the Divisions of Immunology
and Ultrastructural Biology,
Shigei Medical Research Institute, Okayama, Japan; the Department of Molecular Biology and Biochemistry,^§
Okayama University Medical School, Okayama, Japan; and the Department of Pathobiology,^¶
Ontario Veterinary College and University of Guelph, Guelph, Canada

X-linked Alport syndrome is a progressive nephropathy associated with mutations in the COL4A5 gene. The kidney usually lacks the 3-6 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 3, 4, and 5 chains in the kidney, implying a mechanism coordinating the production of these 3 chains. To examine whether production of 6 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 6 mRNA level remained normal in affected male dog smooth muscle while the 5 mRNA level was markedly reduced. However, both 5 and 6 chains were absent at the protein level. Our results suggest that production of the 6 chain is under a control mechanism separate from that coordinating the 3-5 chains and that the lack of the 6 chain in Alport syndrome is related to a failure at the protein assembly level, raising the possibility that the 5 and 6 chains are present in the same network. The lack of the 6 chain does not obviously result in disease, in particular leiomyomatosis, as is seen in Alport patients with deletions involving the COL4A5 and COL4A6 genes.

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