Disease relevance of COL1A1

• Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma [1].
• Amplified cDNAs prepared from lymphoblastoid cells were used to identify previously characterized heterozygous mutations in the COL1A1 and COL1A2 genes from two patients with osteogenesis imperfecta and in the COL3A1 gene from a patient with the Ehlers-Danlos syndrome type IV [2].
• Lack of association between osteoarthritis of the hip and gene polymorphisms of VDR, COL1A1, and COL2A1 in postmenopausal women [3].
• The data obtained exclude linkage of Marfan syndrome to the two major fibrillar collagen (COL1A1, COL1A2, and COL2A1) genes [4].
• The allele frequency of the G-->T mutation of COL1A1 gene (collagen type I alpha 1 gene, GenBank accession n. AF017178) was analyzed by a newARMS-PCR method in 240 osteoporotic subjects bearing a femoral neck fracture [5].

High impact information on COL1A1

• COL1A1 is a major constituent of the connective tissue matrix [1].
• Here we describe efficient and reproducible gene targeting in fetal fibroblasts to place a therapeutic transgene at the ovine alpha1(I) procollagen (COL1A1) locus and the production of live sheep by nuclear transfer [6].
• The authors found a novel missense mutation in COL1A1, the gene encoding the alpha1 chain of type I collagen, in all affected individuals in 3 discrete pedigrees [7].
• Affected individuals and obligate carriers were heterozygous for a missense mutation (3040Ctwo head right arrowT) in exon 41 of the gene encoding the alpha1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain [8].
• A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders [8].

Chemical compound and disease context of COL1A1

• We have previously shown that hypoxia (2% O2), when compared to standard oxygen tension (20% O2), upregulates the mRNA levels of the human alpha1(I) (COL1A1) procollagen gene and transforming growth factor-beta1 (TGF-beta1) in human dermal fibroblasts [9].
• TNF-alpha inhibited the CAT activity of fibroblasts transfected with plasmids containing 2.3 kb of 5' flanking sequences of COL1A1, whereas the activity of control plasmids containing the herpes simplex thymidine kinase promoter gene (pBLCAT) was unaltered [10].
• OBJECTIVE: To evaluate the effects of mithramycin on COL1A1 expression in systemic sclerosis fibroblasts [11].
• Detection of COL1A1-PDGFB fusion transcripts in dermatofibrosarcoma protuberans by reverse transcription-polymerase chain reaction using archival formalin-fixed, paraffin-embedded tissues [12].

Biological context of COL1A1

• Frameshift mutation near the 3' end of the COL1A1 gene of type I collagen predicts an elongated Pro alpha 1(I) chain and results in osteogenesis imperfecta type I [13].
• Thus, in contrast to mutations in genes that encode the dominant protein of a tissue (e.g., COL1A1 and COL2A1), in which "null" mutations result in phenotypes milder than those caused by mutations that alter protein sequence, the phenotypes produced by these mutations in COL3A1 overlap with those of the vascular form of EDS [14].
• The two genes of type I collagen, COL1A1 and COL2A1, have been mapped previously to chromosomes 17 and 7, respectively [15].
• Variable expression of osteogenesis imperfecta in a nuclear family is explained by somatic mosaicism for a lethal point mutation in the alpha 1(I) gene (COL1A1) of type I collagen in a parent [16].
• To assay the genomic DNA, we established a consensus sequence for the first 12 kb of the COL1A1 gene and for 30 kb of new sequences of the 38-kb COL1A2 gene [17].

Anatomical context of COL1A1

• By allele-specific oligonucleotide hybridization to amplified genomic sequences from paternal tissues we determined that the mutant allele accounted for approximately 50% of the COL1A1 alleles in fibroblasts, 27% of those in blood, and 37% of those in sperm [16].
• Collagen produced from osteoblasts cultured from "Ss" heterozygotes had an increased ratio of alpha 1(I) protein relative to alpha 2(I), and this was accompanied by an increased ratio of COL1A1 mRNA relative to COL1A2 [18].
• NIH-3T3 cells were simultaneously transfected with a Tax expressor plasmid and a chimeric construct containing regulatory sequences (-804 to +42 bp) of the alpha 1(I) procollagen gene (COL1A1) promoter [19].
• Here we show that the hammerhead ribozyme Rzpol1a1, targeting a common polymorphism within transcripts from the COL1A1 gene, downregulates COL1A1 transcript in human mesenchymal progenitor cells at a ribozyme to transcript ratio of only 1:1 [20].
• These results suggest that cis sequences found in ColCAT3.6 mediate high levels of COL1A1 expression in bone and tendon, but not in vascular smooth muscle cells (VSMC), whereas sequences located within the minigene, but not found in ColCAT3.6, mediate VSMC-specific expression [21].

Associations of COL1A1 with chemical compounds

• Subsequent amplification of the cDNA by the PCR and nucleotide sequencing revealed a single-base mutation that substituted an aspartate codon for glycine at position alpha 1-541 in the COL1A1 gene [22].
• The nucleotide sequence of a fragment amplified from genomic DNA confirmed the location of the cysteine residue and showed that the mutation was a single nucleotide change in one COL1A1 allele [23].
• Inhibition of basal and transforming growth factor-beta-induced stimulation of COL1A1 transcription by the DNA intercalators, mitoxantrone and WP631, in cultured human dermal fibroblasts [24].
• The individual was heterozygous for a G to A transition in the COL1A1 gene that resulted in the substitution of serine for glycine 883 in one or both of the pro alpha 1 (I) chains [25].
• Cyanogen bromide cleavage and subsequent sequencing revealed a G-to-T base substitution at nucleotide 2420 of COL1A1, resulting in a Gly586Val substitution [26].

Physical interactions of COL1A1

• CONCLUSION: Some cases of otosclerosis and osteoporosis could share a functionally significant polymorphism in the Sp1 transcription factor binding site in the first intron of the COL1A1 gene [27].
• Association of otosclerosis with Sp1 binding site polymorphism in COL1A1 gene: evidence for a shared genetic etiology with osteoporosis [27].

Regulatory relationships of COL1A1

• Competition of the drugs for Sp1 binding and their effect on TGF-beta-induced stimulation of COL1A1 transcription was also examined [24].
• In addition, by employing full-length or deleted B-Myb cDNA construct, we found that B-Myb down-regulates the COL1A1 proximal promoter through its C-terminal domain [28].
• The results indicate that IFN-gamma inhibits COL1A1 expression in fibroblasts principally at the level of gene transcription [29].
• A 1.9-Kb 5' fragment from the human COL1A1 gene drives inappropriate expression of the human COL2A1 gene in tissues of transgenic mice that normally express only the COL1A1 gene [30].
• METHODS: Nuclear extracts from dermal fibroblasts from 4 patients with SSc and 4 age- and sex-matched control individuals were examined by electrophoresis mobility shift assays with a COL1A1 promoter fragment encompassing nucleotides -174 to -50 bp [31].

Other interactions of COL1A1

• It is interesting that such glycine substitutions inside the COL1A1 or COL1A2 genes have been associated with many cases of osteogenesis imperfecta [32].
• In this study, we analyzed the regulation of the alpha1(I) procollagen (COL1A1) promoter and the alpha2(I) procollagen (COL1A2) promoter by IL-4 in normal human lung fibroblasts [33].
• Sequence analysis revealed that the ends of exons 42, 29 and 38 in the COL1A1 gene were fused with the start of exon 2 in the PDGFB gene in case 1, 2 and 3, respectively [34].
• Polymorphisms were detected by digestion with Bsm I for VDR, Acc B7I for COL1A1, and Pvu II for COL2A1 [3].
• The Sp1 transcription factor plays a crucial role in COL1A1 transcriptional regulation under normal and pathologic conditions and under the effects of transforming growth factor-beta (TGF-beta) [24].

Analytical, diagnostic and therapeutic context of COL1A1

• Collagen production was examined by enzyme-linked immunosorbent assay and metabolic labeling, COL1A1 steady-state mRNA levels, and stability were assessed by Northern hybridizations, and COL1A1 transcription by in vitro nuclear transcription assays and transient transfections [24].
• We describe a dominant point mutation in the COL1A1 gene causing extremely severe osteogenesis imperfecta (OI type II/III) which was detected in the dermal fibroblasts of a proband, diagnosed by ultrasonography at 24 weeks of gestation [35].
• Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture [36].
• Northern-blot analysis showed an inverse relationship between COL1A1 mRNA expression and that of B-Myb during exponential cell growth and during quiescence in human SSc fibroblasts [28].
• The DNA binding activity of nuclear proteins recognizing the regulatory regions in the COL1A1 promoter was examined by gel mobility shift assays [37].

References