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Gene Review

COL1A1  -  collagen, type I, alpha 1

Homo sapiens

Synonyms: Alpha-1 type I collagen, Collagen alpha-1(I) chain, OI4
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Disease relevance of COL1A1


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


Biological context of COL1A1


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


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


  1. Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Simon, M.P., Pedeutour, F., Sirvent, N., Grosgeorge, J., Minoletti, F., Coindre, J.M., Terrier-Lacombe, M.J., Mandahl, N., Craver, R.D., Blin, N., Sozzi, G., Turc-Carel, C., O'Brien, K.P., Kedra, D., Fransson, I., Guilbaud, C., Dumanski, J.P. Nat. Genet. (1997) [Pubmed]
  2. Low basal transcription of genes for tissue-specific collagens by fibroblasts and lymphoblastoid cells. Application to the characterization of a glycine 997 to serine substitution in alpha 1(II) collagen chains of a patient with spondyloepiphyseal dysplasia. Chan, D., Cole, W.G. J. Biol. Chem. (1991) [Pubmed]
  3. Lack of association between osteoarthritis of the hip and gene polymorphisms of VDR, COL1A1, and COL2A1 in postmenopausal women. Aerssens, J., Dequeker, J., Peeters, J., Breemans, S., Boonen, S. Arthritis Rheum. (1998) [Pubmed]
  4. Linkage analysis of five fibrillar collagen loci in a large French Marfan syndrome family. Boileau, C., Jondeau, G., Bonaiti, C., Coulon, M., Delorme, G., Dubourg, O., Bourdarias, J.P., Junien, C. J. Med. Genet. (1990) [Pubmed]
  5. Allele frequency of the G-->T mutation of the col1A1 gene analyzed by an ARMS-PCR in osteoporotic subjects with femoral neck fractures. Montanaro, L., Arciola, C.R. Clin. Chem. Lab. Med. (2002) [Pubmed]
  6. Production of gene-targeted sheep by nuclear transfer from cultured somatic cells. McCreath, K.J., Howcroft, J., Campbell, K.H., Colman, A., Schnieke, A.E., Kind, A.J. Nature (2000) [Pubmed]
  7. Caffey disease: an unlikely collagenopathy. Glorieux, F.H. J. Clin. Invest. (2005) [Pubmed]
  8. A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. Gensure, R.C., Mäkitie, O., Barclay, C., Chan, C., Depalma, S.R., Bastepe, M., Abuzahra, H., Couper, R., Mundlos, S., Sillence, D., Ala Kokko, L., Seidman, J.G., Cole, W.G., Jüppner, H. J. Clin. Invest. (2005) [Pubmed]
  9. Low oxygen tension stimulates collagen synthesis and COL1A1 transcription through the action of TGF-beta1. Falanga, V., Zhou, L., Yufit, T. J. Cell. Physiol. (2002) [Pubmed]
  10. The transcription of human alpha 1(I) procollagen gene (COL1A1) is suppressed by tumour necrosis factor-alpha through proximal short promoter elements: evidence for suppression mechanisms mediated by two nuclear-factorbinding sites. Mori, K., Hatamochi, A., Ueki, H., Olsen, A., Jimenez, S.A. Biochem. J. (1996) [Pubmed]
  11. Inhibition of collagen gene expression in systemic sclerosis dermal fibroblasts by mithramycin. Sandorfi, N., Louneva, N., Hitraya, E., Hajnoczky, G., Saitta, B., Jimenez, S.A. Ann. Rheum. Dis. (2005) [Pubmed]
  12. Detection of COL1A1-PDGFB fusion transcripts in dermatofibrosarcoma protuberans by reverse transcription-polymerase chain reaction using archival formalin-fixed, paraffin-embedded tissues. Wang, J., Hisaoka, M., Shimajiri, S., Morimitsu, Y., Hashimoto, H. Diagn. Mol. Pathol. (1999) [Pubmed]
  13. 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. Willing, M.C., Cohn, D.H., Byers, P.H. J. Clin. Invest. (1990) [Pubmed]
  14. Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV. Schwarze, U., Schievink, W.I., Petty, E., Jaff, M.R., Babovic-Vuksanovic, D., Cherry, K.J., Pepin, M., Byers, P.H. Am. J. Hum. Genet. (2001) [Pubmed]
  15. Chromosomal assignments of the genes coding for human types II, III, and IV collagen: a dispersed gene family. Solomon, E., Hiorns, L.R., Spurr, N., Kurkinen, M., Barlow, D., Hogan, B.L., Dalgleish, R. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  16. 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. Wallis, G.A., Starman, B.J., Zinn, A.B., Byers, P.H. Am. J. Hum. Genet. (1990) [Pubmed]
  17. 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. Körkkö, J., Ala-Kokko, L., De Paepe, A., Nuytinck, L., Earley, J., Prockop, D.J. Am. J. Hum. Genet. (1998) [Pubmed]
  18. A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. Mann, V., Hobson, E.E., Li, B., Stewart, T.L., Grant, S.F., Robins, S.P., Aspden, R.M., Ralston, S.H. J. Clin. Invest. (2001) [Pubmed]
  19. Stimulation of alpha 1 (I) procollagen gene expression in NIH-3T3 cells by the human T cell leukemia virus type 1 (HTLV-1) Tax gene. Muñoz, E., Suri, D., Amini, S., Khalili, K., Jiménez, S.A. J. Clin. Invest. (1995) [Pubmed]
  20. Validation in mesenchymal progenitor cells of a mutation-independent ex vivo approach to gene therapy for osteogenesis imperfecta. Millington-Ward, S., Allers, C., Tuohy, G., Conget, P., Allen, D., McMahon, H.P., Kenna, P.F., Humphries, P., Farrar, G.J. Hum. Mol. Genet. (2002) [Pubmed]
  21. Regulation of the alpha 1(I) collagen promoter in vascular smooth muscle cells. Comparison with other alpha 1(I) collagen-producing cells in transgenic animals and cultured cells. Bedalov, A., Breault, D.T., Sokolov, B.P., Lichtler, A.C., Bedalov, I., Clark, S.H., Mack, K., Khillan, J.S., Woody, C.O., Kream, B.E. J. Biol. Chem. (1994) [Pubmed]
  22. A single base mutation in type I procollagen (COL1A1) that converts glycine alpha 1-541 to aspartate in a lethal variant of osteogenesis imperfecta: detection of the mutation with a carbodiimide reaction of DNA heteroduplexes and direct sequencing of products of the PCR. Zhuang, J.P., Constantinou, C.D., Ganguly, A., Prockop, D.J. Am. J. Hum. Genet. (1991) [Pubmed]
  23. Substitution of cysteine for glycine within the carboxyl-terminal telopeptide of the alpha 1 chain of type I collagen produces mild osteogenesis imperfecta. Cohn, D.H., Apone, S., Eyre, D.R., Starman, B.J., Andreassen, P., Charbonneau, H., Nicholls, A.C., Pope, F.M., Byers, P.H. J. Biol. Chem. (1988) [Pubmed]
  24. 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. Gaidarova, S., Jiménez, S.A. J. Biol. Chem. (2002) [Pubmed]
  25. Substitution of serine for glycine 883 in the triple helix of the pro alpha 1 (I) chain of type I procollagen produces osteogenesis imperfecta type IV and introduces a structural change in the triple helix that does not alter cleavage of the molecule by procollagen N-proteinase. Lightfoot, S.J., Atkinson, M.S., Murphy, G., Byers, P.H., Kadler, K.E. J. Biol. Chem. (1994) [Pubmed]
  26. (G586V) substitutions in the alpha 1 and alpha 2 chains of collagen I: effect of alpha-chain stoichiometry on the phenotype of osteogenesis imperfecta? Lund, A.M., Skovby, F., Schwartz, M. Hum. Mutat. (1997) [Pubmed]
  27. Association of otosclerosis with Sp1 binding site polymorphism in COL1A1 gene: evidence for a shared genetic etiology with osteoporosis. McKenna, M.J., Nguyen-Huynh, A.T., Kristiansen, A.G. Otol. Neurotol. (2004) [Pubmed]
  28. B-Myb acts as a repressor of human COL1A1 collagen gene expression by interacting with Sp1 and CBF factors in scleroderma fibroblasts. Cicchillitti, L., Jimenez, S.A., Sala, A., Saitta, B. Biochem. J. (2004) [Pubmed]
  29. Negative modulation of alpha1(I) procollagen gene expression in human skin fibroblasts: transcriptional inhibition by interferon-gamma. Yuan, W., Yufit, T., Li, L., Mori, Y., Chen, S.J., Varga, J. J. Cell. Physiol. (1999) [Pubmed]
  30. 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. Ala-Kokko, L., Yuan, C.M., Le Guellec, D., Franc, S., Fertala, A., Khillan, J.S., Sokolov, B.P., Prockop, D.J. Ann. N. Y. Acad. Sci. (1996) [Pubmed]
  31. CCAAT binding transcription factor binds and regulates human COL1A1 promoter activity in human dermal fibroblasts: demonstration of increased binding in systemic sclerosis fibroblasts. Saitta, B., Gaidarova, S., Cicchillitti, L., Jimenez, S.A. Arthritis Rheum. (2000) [Pubmed]
  32. Substitution of arginine for glycine 325 in the collagen alpha 5 (IV) chain associated with X-linked Alport syndrome: characterization of the mutation by direct sequencing of PCR-amplified lymphoblast cDNA fragments. Knebelmann, B., Deschenes, G., Gros, F., Hors, M.C., Grünfeld, J.P., Zhou, J., Tryggvason, K., Gubler, M.C., Antignac, C. Am. J. Hum. Genet. (1992) [Pubmed]
  33. Transcriptional activation of the type I collagen genes COL1A1 and COL1A2 in fibroblasts by interleukin-4: analysis of the functional collagen promoter sequences. Büttner, C., Skupin, A., Rieber, E.P. J. Cell. Physiol. (2004) [Pubmed]
  34. Analysis of gene mutations in three cases of dermatofibrosarcoma protuberans (DFSP): ordinary DFSP, DFSP with fibrosarcomatous lesion (DFSP-FS) and lung metastasis of DFSP-FS. Saeki, H., Hoashi, T., Tada, Y., Ashida, R., Kuwano, Y., Le Pavoux, A., Tsunemi, Y., Shikada, J., Torii, H., Kawabata, Y., Kikuchi, K., Tamada, Y., Matsumoto, Y., Tamaki, K. J. Dermatol. Sci. (2003) [Pubmed]
  35. Paternal mosaicism for a COL1A1 dominant mutation (alpha 1 Ser-415) causes recurrent osteogenesis imperfecta. Mottes, M., Gomez Lira, M.M., Valli, M., Scarano, G., Lonardo, F., Forlino, A., Cetta, G., Pignatti, P.F. Hum. Mutat. (1993) [Pubmed]
  36. Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture. Mann, V., Ralston, S.H. Bone (2003) [Pubmed]
  37. Identification of elements in the promoter region of the alpha1(I) procollagen gene involved in its up-regulated expression in systemic sclerosis. Hitraya, E.G., Varga, J., Artlett, C.M., Jiménez, S.A. Arthritis Rheum. (1998) [Pubmed]
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