HGNC Approved Gene Symbol: COL15A1
Cytogenetic location: 9q22.33 Genomic coordinates (GRCh38): 9:98,943,907-99,070,787 (from NCBI)
Myers et al. (1992) isolated a 2.1-kb cDNA clone containing a derived gly-X-Y sequence very different from those of collagen types I through XIV. The protein partially encoded by this clone was named the alpha-1 chain of type XV collagen. Kivirikko et al. (1994) and Muragaki et al. (1994) obtained additional cDNA sequences and deduced the complete primary structure of the polypeptide. The former group also partially characterized the gene structure, while the latter noted strong amino acid sequence similarity to mouse alpha-1(XVIII) collagen (COL18A1; 120328). The presence of a predicted signal peptide suggests that the protein is secreted into the extracellular matrix. Muragaki et al. (1994) also presented evidence for predominant expression in embryonic internal organs such as the adrenal glands, kidney, and pancreas. Types XV and XVIII collagen form a distinct subgroup among the collagens (Muragaki et al., 1994; Rehn et al., 1994). Type XVIII collagen (COL18A1; 120328) is the precursor of endostatin, which has a potent antiangiogenic effect. The highest degree of homology between collagens type XV and type XVIII involves the C-terminal endostatin sequence. The corresponding fragment in type XV collagen has also been shown to have antiangiogenic activity (Ramchandran et al., 1999; Sasaki et al., 2000).
Myers et al. (1996) stated that the collagen family of proteins consists of 19 types encoded by 33 genes. Type XV collagen has a 577-amino acid, highly interrupted, triple-helical region that is flanked by N- and C-terminal noncollagenous domains of 555 and 256 residues, respectively.
Hagg et al. (1998) reported that the COL15A1 protein contains 1,388 amino acids.
Myers et al. (1996) produced a bacteria-expressed recombinant protein representing the first half of the type XV collagen C-terminal domain in order to generate highly specific polyclonal antisera. Northern blot hybridization to human tissue RNAs indicated that type XV has a widespread distribution. To determine the precise localization of type XV collagen, immunohistochemical analyses were performed. A surprisingly restricted and uniform presence was demonstrated in many tissues which showed a strong association with vascular, neuronal, mesenchymal, and some epithelial basement membrane zones. Myers et al. (1996) suggested that type XV collagen may function in some manner to adhere basement membrane to the underlying connective tissue stroma.
Using an antibody produced against the C-terminal noncollagenous domain of human type XV collagen, Hagg et al. (1997) found conspicuous staining of most capillaries and the staining of the basement membrane zones of muscle cells. Differences in the expression of type XV collagen could be observed during kidney development, and staining of fetal lung tissue suggested that changes in its expression may also occur during the formation of vascular structures. Pronounced renal interstitial type XV collagen staining was observed in patients with kidney fibrosis occurring as part of different pathologic processes. They suggested that the accumulation of type XV collagen may accompany fibrotic processes.
To understand the biologic role of type XV collagen, Eklund et al. (2001) introduced a null mutation in the Col15a1 gene into the germline of mice. Despite the complete lack of type XV collagen, the mutant mice developed and reproduced normally, and they were indistinguishable from their wildtype littermates. However, Col15a1-deficient mice showed progressive histologic changes characteristic for muscular disease after 3 months of age, and they were more vulnerable than controls to exercise-induced muscle injury. Despite the antiangiogenic role of type XV collagen-derived endostatin, the development of the vasculature appeared normal in the null mice. Nevertheless, ultrastructural analyses revealed collapsed capillaries and endothelial cell degeneration in heart and skeletal muscle. Furthermore, perfused hearts showed a diminished inotropic response, and exercise resulted in cardiac injury, changes that mimic early or mild heart disease. Thus, type XV collagen appears to function as a structural component needed to stabilize skeletal muscle cells and microvessels.
Using normal human aortic smooth muscle cells (SMCs) in culture, Connelly et al. (2013) identified 13 SmaI sites (CCCGGG) in the COL15A1 gene that lost methylation with replicative age. These sites clustered in a region upstream of the transcription start site and at the 3-prime end of the gene, within introns 30 and 31 and exon 35. Quantitative real-time PCR of SMCs from a different source confirmed hypomethylation at 2 of these sites with age in culture, concomitant with elevated COL15A1 mRNA and protein. Knockdown of COL15A1 via small interfering RNA reduced SMC proliferation and increased migration. In a mouse model of diet-induced atherosclerosis, expression of Col15a1 was increased in thoracic aorta, and a similar trend was found in human aorta.
By genomic sequence analysis, Hagg et al. (1998) determined that the COL15A1 gene has 42 coding exons spanning 145 kb. The promoter region lacks a TATAA motif, has multiple apparently functional Sp1 (189906)-binding sites, and has several GC motifs similar to the promoters of housekeeping genes. Comparative analysis between COL15A1 and mouse Col18a1 (120328) suggested that the 2 genes are derived from a common ancestor.
By studying DNAs from rodent-human hybrid cells and by in situ hybridization, Huebner et al. (1992) assigned the gene to 9q21-q22, a region to which no other collagen genes had previously been assigned. Huebner et al. (1992) stated that this was the twenty-first collagen gene to be localized and that chromosome 9 was the twelfth of the human chromosomes found to contain at least one member of this unusual gene family. Hagg et al. (1997) cloned the mouse gene and mapped it to mouse chromosome 4 in a region of conserved synteny with human chromosome 9q21-q22.
Using light and electron microscopy, Rasi et al. (2010) found that deletion of Col15a1 in mice resulted in disorganized fibrillar collagen bundles in heart, with interstitial deposition of nonfibrillar protein aggregates, abnormal capillary morphology, extravasated erythrocytes, and ischemic damage in some cardiomyocytes. These changes correlated with measurable microvascular and cardiac dysfunction and increased myocardial stiffness. Echocardiograms indicated that the early changes in cardiac performance and geometry in Col15a1 -/- mice varied with age and showed some reversal with age.
Connelly, J. J., Cherepanova, O. A., Doss, J. F., Karaoli, T., Lillard, T. S., Markunas, C. A., Nelson, S., Wang, T., Ellis, P. D., Langford, C. F., Haynes, C., Seo, D. M., Goldschmidt-Clermont, P. J., Shah, S. H., Kraus, W. E., Hauser, E. R., Gregory, S. G. Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis. Hum. Molec. Genet. 22: 5107-5120, 2013. [PubMed: 23912340] [Full Text: https://doi.org/10.1093/hmg/ddt365]
Eklund, L., Piuhola, J., Komulainen, J., Sormunen, R., Ongvarrasopone, C., Fassler, R., Muona, A., Ilves, M., Ruskoaho, H., Takala, T. E. S., Pihlajaniemi, T. Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice. Proc. Nat. Acad. Sci. 98: 1194-1199, 2001. [PubMed: 11158616] [Full Text: https://doi.org/10.1073/pnas.98.3.1194]
Hagg, P. M., Hagg, P. O., Peltonen, S., Autio-Harmainen, H., Pihlajaniemi, T. Location of type XV collagen in human tissues and its accumulation in the interstitial matrix of the fibrotic kidney. Am. J. Path. 150: 2075-2086, 1997. [PubMed: 9176399]
Hagg, P. M., Horelli-Kuitunen, N., Eklund, L., Palotie, A., Pihlajaniemi, T. Cloning of mouse type XV collagen sequences and mapping of the corresponding gene to 4B1-3: comparison of mouse and human alpha-1(XV) collagen sequences indicates divergence in the number of small collagenous domains. Genomics 45: 31-41, 1997. [PubMed: 9339358] [Full Text: https://doi.org/10.1006/geno.1997.4884]
Hagg, P. M., Muona, A., Lietard, J., Kivirikko, S., Pihlajaniemi, T. Complete exon-intron organization of the human gene for the alpha-1 chain of type XV collagen (COL15A1) and comparison with the homologous Col18a1 gene. J. Biol. Chem. 273: 17824-17831, 1998. [PubMed: 9651385] [Full Text: https://doi.org/10.1074/jbc.273.28.17824]
Huebner, K., Cannizzaro, L. A., Jabs, E. W., Kivirikko, S., Manzone, H., Pihlajaniemi, T., Myers, J. C. Chromosomal assignment of a gene encoding a new collagen type (COL15A1) to 9q21-q22. Genomics 14: 220-224, 1992. [PubMed: 1427836] [Full Text: https://doi.org/10.1016/s0888-7543(05)80209-5]
Kivirikko, S., Heinamaki, P., Rehn, M., Honkanen, N., Myers, J. C., Pihlajaniemi, T. Primary structure of the alpha-1 chain of human type XV collagen and exon-intron organization in the 3-prime region of the corresponding gene. J. Biol. Chem. 269: 4773-4779, 1994. [PubMed: 8106446]
Muragaki, Y., Abe, N., Ninomiya, Y., Olsen, B. R., Ooshima, A. The human alpha-1(XV) collagen chain contains a large amino-terminal non-triple helical domain with a tandem repeat structure and homology to alpha-1(XVIII) collagen. J. Biol. Chem. 269: 4042-4046, 1994. [PubMed: 8307960]
Myers, J. C., Dion, A. S., Abraham, V., Amenta, P. S. Type XV collagen exhibits a widespread distribution in human tissues but a distinct localization in basement membrane zones. Cell Tissue Res. 286: 493-505, 1996. [PubMed: 8929352] [Full Text: https://doi.org/10.1007/s004410050719]
Myers, J. C., Kivirikko, S., Gordon, M. K., Dion, A. S., Pihlajaniemi, T. Identification of a previously unknown human collagen chain, alpha-1(XV), characterized by extensive interruptions in the triple-helical region. Proc. Nat. Acad. Sci. 89: 10144-10148, 1992. [PubMed: 1279671] [Full Text: https://doi.org/10.1073/pnas.89.21.10144]
Ramchandran, R., Dhanabal, M., Volk, R., Waterman, M. J. F., Segal, M., Lu, H., Knebelmann, B., Sukhatme, V. P. Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin. Biochem. Biophys. Res. Commun. 255: 735-739, 1999. [PubMed: 10049780] [Full Text: https://doi.org/10.1006/bbrc.1999.0248]
Rasi, K., Piuhola, J., Czabanka, M., Sormunen, R., Ilves, M., Leskinen, H., Rysa, J., Kerkela, R., Janmey, P., Heljasvaara, R., Peuhkurinen, K., Vuolteenaho, O., Ruskoaho, H., Vajkoczy, P., Pihlajaniemi, T., Eklund, L. Collagen XV is necessary for modeling of the extracellular matrix and its deficiency predisposes to cardiomyopathy. Circ. Res. 107: 1241-1252, 2010. [PubMed: 20847313] [Full Text: https://doi.org/10.1161/CIRCRESAHA.110.222133]
Rehn, M., Hintikka, E., Pihlajaniemi, T. Primary structure of the alpha 1 chain of mouse type XVIII collagen, partial structure of the corresponding gene, and comparison of the alpha 1(XVIII) chain with its homologue, the alpha 1(XV) collagen chain. J. Biol. Chem. 269: 13929-13935, 1994. [PubMed: 8188673]
Sasaki, T., Larsson, H., Tisi, D., Claesson-Welsh, L., Hohenester, E., Timpl, R. Endostatins derived from collagens XV and XVIII differ in structural and binding properties, tissue distribution and anti-angiogenic activity. J. Molec. Biol. 301: 1179-1190, 2000. [PubMed: 10966814] [Full Text: https://doi.org/10.1006/jmbi.2000.3996]