The genes for the alpha 1(IV) and alpha 2(IV) chains of human basement membrane collagen type IV are arranged head-to-head and separated by a bidirectional promoter of unique structure.

Abstract

The human basement membrane specific collagen type IV is a heterotrimer composed of two alpha 1(IV) chains and one alpha 2(IV) chain. A partial genomic EcoRI library was screened with cDNA clones representing the 5′ end regions of the alpha 1(IV) and the alpha 2(IV) mRNA. A 2.2‐kb genomic fragment was isolated and sequenced, which contains the 5′ terminal exons of both genes located in close vicinity. The two genes were found to be arranged in opposite direction, head‐to‐head, separated only by a short region of 127 bp, apparently representing promoters of both genes as indicated by the existence of typical sequence motifs (CAT‐box, SP1 consensus sequence). These data suggest that the alpha 1(IV) and alpha 2(IV) genes use a common, bidirectional promoter. The striking symmetrical arrangement of sequence elements within the promoter may be of basic importance for the coordination of bidirectional transcription. The promoter region had no detectable transcriptional activity in transient gene expression assays after fusion to the chloramphenicol acetylase (CAT) gene in either direction, indicating the necessity of additional elements for efficient and tissue‐specific expression of both genes. Constructs containing different segments of both genes failed to identify regions with enhancing activity for the homologous collagen type IV promoter. When the heterologous HSV thymidine kinase promoter was used, a negatively acting region was identified. This indicates that the alpha 1(IV) and alpha 2(IV) promoter activity is controlled by additional regulatory elements present on distant portions of both genes.

Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development

“…Targeted inactivation of the Col4a1/Col4a2 genes does not interfere with early embryonic development The Col4a1 and Col4a2 genes are closely linked on mouse chromosome 8 in a unique head-to-head arrangement and separated by a short, shared promoter region similar to the human genes (Burbelo et al, 1988;Pöschl et al, 1988). The first exon of Col4a1 and exons 1-3 of Col4a2 encode the 5′ untranslated regions together with the signal peptides, respectively.…”

Comparative distribution of the alpha 1(IV), alpha 5(IV), and alpha 6(IV) collagen chains in normal human adult and fetal tissues and in kidneys from X-linked Alport syndrome patients.

“…The al(IV) and a2(IV) gene pair and a3 (IV) and a4(IV) gene pair are located on chromosome 13 (36)(37)(38) and chromosome 2q35-37 (39), respectively. Exactly the same head-to-head genomic arrangement has been found in the mouse for the a1 (IV) and a2 (IV) genes (40,41 ).…”

Molecular cloning of the human Goodpasture antigen demonstrates it to be the alpha 3 chain of type IV collagen.

“…The possibility that mutations in another type IV collagen chain mapping to the same locus could produce the disease is suggested by the extremely close, head-to-head arrangement of the a 1 and a2 chain genes on chromosome 13 (46,47). However, a direct role for the a3 chain in most cases of Alport's syndrome is ruled out by our observation that its gene maps to chromosome 2.…”