Disease relevance of COL7A1

• A naturally occurring deletion in the human COL7A1 gene, 8523del14, which is associated with dystrophic epidermolysis bullosa and eliminates the BMP-1 consensus sequence, abolished processing of procollagen VII, and in mutant skin procollagen VII accumulated at the dermal-epidermal junction [1].
• Pretibial epidermolysis bullosa: genetic linkage to COL7A1 and identification of a glycine-to-cysteine substitution in the triple-helical domain of type VII collagen [2].
• Mutations in the type VII collagen gene, COL7A1, give rise to the blistering skin disease, dystrophic epidermolysis bullosa [3].
• We demonstrated that gene transfer using a combination of G protein of vesicular stomatitis virus-pseudotyped retroviral vector and retronectin introduced COL7A1 into keratinocytes and fibroblasts from a DEB patient with the lack of COL7A1 expression [4].
• BACKGROUND: Dystrophic epidermolysis bullosa (DEB) is a bullous skin disease caused by mutations in the type VII collagen gene (COL7A1) [5].

High impact information on COL7A1

• Dystrophic epidermolysis bullosa (DEB) is a family of inherited mechano-bullous disorders caused by mutations in the human type VII collagen gene (COL7A1) [6].
• Transduction of lentiviral vectors containing the COL7A1 transgene into recessive DEB (RDEB) keratinocytes and fibroblasts (in which type VII collagen was absent) resulted in persistent synthesis and secretion of type VII collagen [6].
• Ultrastructural observations of altered anchoring fibrils and genetic linkage to the type VII collagen locus (COL7A1) have implicated COL7A1 as the candidate gene in the dystrophic forms of EB [7].
• The patients are compound heterozygotes for two different mutations, both of which result in a premature termination codon in COL7A1, and the parents were shown to be clinically heterozygous carries of the respective mutations [7].
• Since there were no recombinants between the COL7A1 and EBDD loci, our findings suggest that type VII collagen is the candidate gene that may harbor the mutations responsible for the EB phenotype in these three families [8].

Biological context of COL7A1

• The recessive dystrophic epidermolysis bullosa patients had a homozygous single base-pair frameshift mutation in exon 19 of COL7A1 (2470insG) [9].
• Finally, the major, if not the exclusive, component of anchoring fibrils is type VII collagen, encoded by the gene (COL7A1) which consists of 118 distinct exons, the largest number of exons in any gene published thus far [10].
• Inspection of the locations of the glycine substitutions along the COL7A1 polypeptide suggests that the consequences of these mutations, in terms of phenotype and pattern of inheritance, are position independent [11].
• We have recently demonstrated tight genetic linkage between the type VII collagen gene (COL7A1) and both the dominant and recessive forms of dystrophic EB [12].
• Patients who were homozygous or compound heterozygotes for mutations leading to PTCs displayed both absence or drastic reduction of COL7A1 transcripts and undetectable type VII collagen protein in skin [13].

Anatomical context of COL7A1

• Consistent with the normal levels of COL7A1 mRNA transcripts detected by northern analysis, immunoblotting and immunofluorescence studies evidenced that the patient keratinocytes synthesize and secrete normal amounts of stable type VII collagen, which is correctly deposited at the dermal-epidermal junction [14].
• Mutations in the gene COL7A1 encoding type VII collagen cause dystrophic epidermolysis bullosa, a clinically heterogeneous autosomal dominant or recessive blistering disorder of the skin and mucous membranes [14].
• Previous studies have shown that pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta up-regulate type VII collagen gene (COL7A1) expression in cultured dermal fibroblasts [15].
• Toenail dystrophy with COL7A1 glycine substitution mutations segregates as an autosomal dominant trait in 2 families with dystrophic epidermolysis bullosa [16].
• Polymerase chain reaction and sequencing of the cDNA, reverse transcribed from the proband's peripheral lymphocyte RNA, suggest that this mutation causes aberrant COL7A1 mRNA splicing of exon 87 skipping [17].

Associations of COL7A1 with chemical compounds

• Mutation detection of the COL7A1 gene revealed a G-->A transition at nucleotide position 6110 in the mutant allele converting a glycine to glutamic acid (G2037E) [18].
• All exons in the COL7A1 triple helix coding region that do not begin with sequences corresponding to imperfections of the triple helix begin with intact codons for Gly residues of Gly-X-Y repeats [19].
• In this study, we have examined the pharmacological control of COL7A1 gene expression by the glucocorticorticoid dexamethasone [20].
• To gain insight into the molecular mechanisms underlying the up-regulation of COL7A1 by this growth factor, we performed transient cell transfections with a series of 5'-deletion promoter/chloramphenicol acetyltransferase reporter gene constructs [21].
• The study revealed a G-to-A transition at nucleotide 6724 within exon 85 of COL7A1, converting a glycine to an arginine (G2242R) within the triple-helical domain of the type VII collagen in affected individuals [22].

Physical interactions of COL7A1

• Deletion analysis of the TGF-betaresponsive region of the COL7A1 promoter by EMSA identified segment -496/-444 as the minimal fragment capable of binding the TGF-beta-induced complex [21].

Other interactions of COL7A1

• In the recessive dystrophic epidermolysis bullosa patients, transcripts containing in-frame skipping of exon 19 of COL7A1 in the cDNA were detected, and in the junctional epidermolysis bullosa patients transcripts with in-frame skipping of exon 17 of LAMB3 were identified [9].
• SMAD3/4-dependent transcriptional activation of the human type VII collagen gene (COL7A1) promoter by transforming growth factor beta [23].
• We also demonstrate that the SMAD binding sequence (SBS) representing the TGF-beta response element in the region -496/-444 of the COL7A1 promoter functions as an enhancer in the context of a heterologous promoter [23].
• Identification of COL7A1 alternative splicing inserting 9 amino acid residues into the fibronectin type III linker domain [24].
• The present study was designed to investigate the effects of TNF-alpha and IL-1beta on COL7A1 expression in epidermal keratinocytes [15].

Analytical, diagnostic and therapeutic context of COL7A1

• We searched for mutations in dominant dystrophic EB by PCR amplification of genomic segments of COL7A1, followed by heteroduplex analysis [12].
• Sequence analysis revealed a G-->A transition at nucleotide 6118 in the triple helical domain of COL7A1, which converted a glycine residue to a serine (GGT-->AGT) [12].
• The genomic location of the type VII collagen gene (COL7A1) was determined by chromosomal in situ hybridization with the K-131 cDNA [25].
• The complete cDNA sequence and polymorphisms in COL7A1 will facilitate mutational analysis and prenatal diagnosis for patients with the dystrophic forms of epidermolysis bullosa, in which mutations in COL7A1 have been demonstrated [26].
• Mutation analysis using polymerase chain reaction amplification of genomic DNA, heteroduplex analysis and direct nucleotide sequencing demonstrated pathogenetic COL7A1 mutations in each case [27].

References