Disease relevance of COL1A2

• Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway [1].
• Mutation in a gene for type I procollagen (COL1A2) in a woman with postmenopausal osteoporosis: evidence for phenotypic and genotypic overlap with mild osteogenesis imperfecta [2].
• In general, osteogenesis imperfecta (brittle bone disease) is caused by heterozygous mutations in the genes encoding the alpha 1 or alpha 2 chains of type I collagen (COL1A1 and COL1A2, respectively) [3].
• Association of COL1A2, COL2A1 and COL9A1 and primary osteoarthritis in a founder population [4].
• Collagen type I alpha2 (COL1A2) is the susceptible gene for intracranial aneurysms [5].

High impact information on COL1A2

• 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 [6].
• Linkage of COL1A2 collagen gene to cystic fibrosis, and its clinical implications [7].
• Splice site mutations in the COL1A2 gene of type I collagen can give rise to forms of Ehlers-Danlos syndrome (EDS) because of partial or complete skipping of exon 6, as well as to mild, moderate, or lethal forms of osteogenesis imperfecta as a consequence of skipping of other exons [1].
• 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 [8].
• Partial isodisomy for maternal chromosome 7 and short stature in an individual with a mutation at the COL1A2 locus [9].

Biological context of COL1A2

• Furthermore, transforming growth factor-beta induced type I collagen alpha 2 chain gene expression in c-myb(-/-) MEFs, implying that the transforming growth factor-beta signaling pathway is maintained and that the absence of COL1A2 gene expression in c-myb(-/-) MEFs is a direct consequence of the lack of c-Myb [10].
• Using human fibroblasts transfected with a alpha2(I) collagen promoter/reporter gene construct (COL1A2), C(6)-ceramide (10 microm) exerted a stimulatory effect on basal and TGF-beta-induced activity of this promoter [11].
• Characterization of point mutations in the collagen COL1A1 and COL1A2 genes causing lethal perinatal osteogenesis imperfecta [12].
• In this paper, we demonstrate that COL1A1 has an RFX consensus binding site surrounding the transcription start site (-11 to +10) that contains three methylation sites rather than one in the COL1A2 gene RFX binding site [13].
• Moreover, a short sequence encompassing the three footprints was found to inhibit expression of transgenic constructs containing the COL1A2 proximal promoter and far upstream enhancer in a position-independent manner [14].

Anatomical context of COL1A2

• The pro alpha 2(I) collagen (COL1A2, in band 7q22) and T cell receptor beta chain genes (TCRB, in band 7q35) have been found undeleted in one patient with an interstitial deletion [15].
• We previously showed that Smad3 promotes COL1A2 gene activation by TGF-beta1 in human mesangial cells [16].
• To study how intracellular oxidative stress modulates alpha 2 collagen type I (COL1A2) gene induction, a rat HSC line (HSC-T6) was transfected with human CYP2E1 complementary DNA in the sense and antisense orientation and with empty vector, and stable cell lines were generated [17].
• This marker may be useful in the prenatal diagnosis of inherited connective tissue diseases in which the COL1A2 gene is involved [18].
• Patients with COL1A1 mutations more frequently had blue scleras than those with COL1A2 mutations [19].

Associations of COL1A2 with chemical compounds

• It is interesting that such glycine substitutions inside the COL1A1 or COL1A2 genes have been associated with many cases of osteogenesis imperfecta [20].
• A child with a moderately severe form of osteogenesis imperfecta was heterozygous for a G to T transition that resulted in a substitution of cysteine for glycine at position 259 in the COL1A2 gene [21].
• S-adenosylmethionine blocks collagen I production by preventing transforming growth factor-beta induction of the COL1A2 promoter [22].
• The mutation was identified as a G to A transition in the COL1A2 gene, which converts glycine 700 to aspartic acid in the alpha 2I chain [23].
• Arginine for glycine substitution in the triple-helical domain of the products of one alpha 2(I) collagen allele (COL1A2) produces the osteogenesis imperfecta type IV phenotype [24].

Physical interactions of COL1A2

• The RFX family interacts at the collagen (COL1A2) start site and represses transcription [25].
• The importance of Smad binding to the CAGACA box of COL1A2 was further established by transcriptional decoy oligonucleotide competition [26].
• An AP-1 binding sequence is essential for regulation of the human alpha2(I) collagen (COL1A2) promoter activity by transforming growth factor-beta [27].
• The results demonstrated that IFN-gamma caused increased C/EBPbeta expression in dermal fibroblasts and enhanced its binding to cognate DNA sequences in the alpha2(I) procollagen gene (COL1A2) promoter in vitro and in vivo [28].
• However, in presence of TSA, TGF-beta fails to induce Sp1 levels, its interaction with Smad complex and Sp1 binding site in COL1A2 promoter [29].

Enzymatic interactions of COL1A2

• RFX1 represses the unmethylated COL1A1 less efficiently than COL1A2 [13].

Regulatory relationships of COL1A2

• Sphingosine 1-phosphate phosphatase (YSR2) stimulated basal COL1A2 promoter activity and cooperated with TGF-beta in activation of this promoter [11].
• Nuclear run-on assay showed a 3-and-a-half-fold increase in COL1A2 transcription in the cells expressing CYP2E1; stabilization of COL1A2 mRNA was also observed [17].
• In normal fibroblasts, the PI3K inhibitor, LY294002, significantly decreased the basal and the TGF-beta1-induced increased stability of COL1A2 mRNA [30].
• Our studies indicate that the regulatory factor for X-box (RFX) family proteins repress collagen alpha2(I) gene (COL1A2) expression (Xu, Y., Wang, L., Buttice, G., Sengupta, P. K., and Smith, B. D. (2003) J. Biol. Chem. 278, 49134-49144; Xu, Y., Wang, L., Buttice, G., Sengupta, P. K., and Smith, B. D. (2004) J. Biol. Chem. 279, 41319-41332) [31].
• Earlier studies have documented that TNF-alpha inhibits type I collagen gene (COL1A2) expression at the transcriptional level, but the characterization of the transcription factors involved has been elusive [32].

Other interactions of COL1A2

• The transcription start site of the collagen alpha2(1) gene (COL1A2) has a sequence-specific binding site for a DNA methylation-responsive binding protein called regulatory factor for X-box 1 (RFX1) (Sengupta, P. K., Erhlich, M., and Smith, B. D. (1999) J. Biol. Chem. 274, 36649-36655) [25].
• We identified highly conserved sequence elements upstream of the AAUAAA in three human collagen genes, COL1A1, COL1A2, and COL2A1, and demonstrate that these upstream sequence elements (USEs) influence polyadenylation efficiency [33].
• Interferon gamma repression of collagen (COL1A2) transcription is mediated by the RFX5 complex [34].
• Gene trapping identifies inhibitors of oncogenic transformation. The tissue inhibitor of metalloproteinases-3 (TIMP3) and collagen type I alpha2 (COL1A2) are epidermal growth factor-regulated growth repressors [35].
• This mutation is analogous to mutations causing exon skipping in the major collagen genes, COL1A1, COL1A2, and COL3A1, identified in several cases of osteogenesis imperfecta and EDS type IV [36].

Analytical, diagnostic and therapeutic context of COL1A2

• RT-PCR amplification of mRNA coding for alpha 2CB4 revealed a heterozygous deletion of the 108 bp exon 21 of COL1A2 [37].
• The physical proximity of the closely linked pro alpha 2(1)collagen (COL1A2) and erythropoietin (EPO) genes and five loci with no known function was studied by long-range restriction mapping experiments using pulsed-field gel electrophoresis [38].
• This single base change creates a new Bsu36 I (Sau I, Mst II) restriction site detectable in genomic DNA by Southern blot analysis when probed with a COL1A2 fragment [39].
• Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning by conformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15 patients with osteogenesis imperfecta type I: identification of common sequences of null-allele mutations [8].
• The effect of KCs on HSC collagen I involved transcriptional regulation, as determined by nuclear in vitro transcription run-on assays, promoter studies, and Northern blot analysis, while stability of the COL1A1 and COL1A2 mRNA were similar [40].

References