Disease relevance of COL4A6

• The predominant form of Alport syndrome is X-linked; more than 160 different mutations have yet been identified in the type IV collagen alpha 5 chain (COL4A5) gene, located at Xq22-24 head to head to the COL4A6 gene [1].
• A subtype of X-linked Alport syndrome (XLAS) in which diffuse leiomyomatosis is an associated feature reflects deletion mutations involving the adjacent COL4A5 and COL4A6 genes [2].
• In the present study, we examined the expression of the alpha5(IV)/alpha6(IV) chains and the methylation profiles of the bidirectional promoter region of COL4A5/COL4A6 in colon cancer cell lines and colorectal tumor tissues [3].
• The X-linked form of Alport disease, caused by mutations in the COL4A5 or the COL4A6 gene, usually leads to terminal renal failure in males, while affected females have a more variable and moderate phenotype [4].
• Genetic analysis demonstrating deletion of the COL4A5/COL4A6 locus and the discovery of microscopic hematuria implied that the patient could transmit both diffuse leiomyomatosis and the Alport syndrome [5].

High impact information on COL4A6

• The gene encoding alpha 6(IV) collagen, COL4A6, was identified on the human X chromosome in a head-to-head arrangement and within 452 base pairs of the alpha 5(IV) collagen gene, COL4A5 [6].
• We show that a deletion eliminates the first coding exon of COL4A5 and the first two coding exons of COL4A6 [7].
• Here we report the 5' flanking sequences of COL4A5 and COL4A6 and that COL4A6 is transcribed from two alternative promoters in a tissue-specific fashion [8].
• In conclusion, the hypermethylation of the bidirectional promoter region of COL4A5/COL4A6 is one of the events that is responsible for the loss of expression of the alpha5(IV)/alpha6(IV) chains and the remodeling of the epithelial BM during cancer cell invasion [3].
• Transcription start sites for two 5' splice variants of COL4A6 are 1 kilobase apart [9].

Biological context of COL4A6

• The exon size pattern of COL4A6 is highly homologous with that of the human and mouse COL4A2 genes, with 27 of the 46 exons of COL4A6 being identical in size between the genes [10].
• A 3.8-kb fragment upstream of COL4A6 directs reporter gene expression in the esophagus, stomach, and duodenum, whereas a 13.8-kb fragment directs expression in the esophagus only [11].
• The genes COL4A5 and COL4A6, coding for basement membrane collagen chains alpha 5(IV) and alpha 6(IV), are located head-to-head in close proximity on human chromosome Xq22 and COL4A6 is transcribed from two alternative promoters [8].
• The alpha5(IV) gene (COL4A5) and the alpha6(IV) gene (COL4A6) are on chromosome Xq22 and are regulated by a bidirectional promoter [3].
• The detailed structure of the COL4A6 gene and the high heterozygosity microsatellite markers located within the gene will be useful for linkage analysis and familial diagnosis of diseases caused by mutations of this gene [12].

Anatomical context of COL4A6

• Differential expression of two basement membrane collagen genes, COL4A6 and COL4A5, demonstrated by immunofluorescence staining using peptide-specific monoclonal antibodies [13].
• In this study, we used dermal fibroblasts from eight normal individuals and nine males with XLAS to test the hypotheses that COL4A5 mutations increase transcription of COL4A1 and suppress transcription of COL4A6 [14].
• Despite this potential basis for coordinated transcription of the COL4A5 and COL4A6 genes, the alpha6 mRNA level remained normal in affected male dog smooth muscle while the alpha5 mRNA level was markedly reduced [15].
• We investigated the proximal promoter region of COL4A5 and COL4A6 using glomerular visceral epithelial cells, in which COL4A5 alone is transcribed; keratinocytes, in which the genes are co-transcribed; and additional model cell lines [9].
• The other contig, which contains DXS137, is in Xq22.2 by FISH, consistent with cell hybrid analyses and with the finding that it covers the human COL4A5 and COL4A6 genes known to be in that vicinity [16].

Other interactions of COL4A6

• The gene organization of the region coding for the NCl domain is similar to that of the human genes COL4A2, COL4A4 and COL4A6 [17].
• Conditions for polymerase chain-reaction amplification of ten exon regions (Exons 3, 7, 11 through 13, and 15 through 19) of the collagen COL4A5 gene and four exon regions (Exons 2, and 12 through 14) of the COL4A6 gene were sequenced and established in this study [18].

Analytical, diagnostic and therapeutic context of COL4A6

• We analyzed 177 Italian Alport syndrome families by Southern blotting using cDNA probes from both COL4A5 and COL4A6 [19].
• PCR along with Southern hybridization analysis revealed a large deletion of the paired COL4A5 and COL4A6 genes [20].

References