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(American Journal of Pathology. 2003;163:1633-1644.)
© 2003 American Society for Investigative Pathology

A Human-Mouse Chimera of the 345(IV) Collagen Protomer Rescues the Renal Phenotype in Col4a3^-/- Alport Mice

Laurence Heidet^*, Dorin-Bogdan Borza, Mélanie Jouin^*, Mireille Sich^*, Marie-Geneviève Mattei, Yoshikazu Sado, Billy G. Hudson, Nicholas Hastie^¶, Corinne Antignac^*|| and Marie-Claire Gubler^*

From INSERM U574,^* Hôpital Necker-Enfants Malades, Université René Descartes, Paris, France; Faculté de Médecine, INSERM U491, Marseille, France; the Service de Génétique,^|| Hôpital Necker-Enfants Malades, Paris, France; the Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee; the Division of Immunology, Shigei Medical Research Institute, Okayama, Japan; and the Medical Research Council Human Genetics Unit,^¶ Western General Hospital, Edinburgh, Scotland

Collagen IV is a major structural component of basement membranes. In the glomerular basement membrane (GBM) of the kidney, the 3, 4, and 5(IV) collagen chains form a distinct network that is essential for the long-term stability of the glomerular filtration barrier, and is absent in most patients affected with Alport syndrome, a progressive inherited nephropathy associated with mutation in COL4A3, COL4A4, or COL4A5 genes. To investigate, in vivo, the regulation of the expression, assembly, and function of the 345(IV) protomer, we have generated a yeast artificial chromosome transgenic line of mice carrying the human COL4A3-COL4A4 locus. Transgenic mice expressed the human 3 and 4(IV) chains in a tissue-specific manner. In the kidney, when expressed onto a Col4a3^-/- background, the human 3(IV) chain restored the expression of and co-assembled with the mouse 4 and 5(IV) chains specifically at sites where the human 3(IV) was expressed, demonstrating that the expression of all three chains is required for network assembly. The co-assembly of the human and mouse chains into a hybrid network in the GBM restores a functional GBM and rescues the Alport phenotype, providing further evidence that defective assembly of the 3-4-5(IV) protomer, caused by mutations in any of the three chains, is the pathogenic mechanism responsible for the disease. This line of mice, humanized for the 3(IV) collagen chain, will also provide a valuable model for studying the pathogenesis of Goodpasture syndrome, an autoimmune disease caused by antibodies against this chain.

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