Organization and expression of basement membrane collagen IV genes and their roles in human disorders

Six distinct genes have been identified as belonging to the type IV collagen gene family. They can be organized into three sets, i.e., COL4A1/COL4A2, COL4A3/COL4A4, and COL4A5/COL4A6, which are localized on three different chromosomes in humans, 13, 2, and X, respectively. Within each set the genes are aligned head-to-head and their expression is regulated by bidirectional promoters between the genes. Transcriptional regulation of the COL4A1/COL4A2 set has been well characterized. The transcription of COL4A6 seems to be controlled by two alternative promoters. While collagen IV molecules composed of α1 and α2 chains are broadly distributed, molecules comprising combinations of the other four chains, α3-α6, are important components of specialized basement membranes. The precise chain composition of triple-helical molecules assembled from the α3-α6 chains is not entirely clear, but it is hypothesized that α3-α5 chains and α5 and α6 chains form heterotrimeric molecules. Several pieces of evidence indicate that α3/α4/α5 molecules and α5/α6 molecules are components of the basement membrane network. This helps explain the observation that the kidney and skin basement membranes from patients with Alport syndrome caused by mutations in the α5 coding gene, COL4A5, are defective in the α3, α4, and α6 chains together with the α5 chain. Large deletions involving the COL4A5 and COL4A6 genes have been found in rare cases of diffuse leiomyomatosis associated with Alport syndrome.