Abstract
The small dermatan sulfate proteoglycan decorin is involved in the regulation of collagen fibrillogenesis, cell adhesion and migration, and growth factor signaling. In a progeroid patient carrying two point mutations in ß4galactosyltransferase I (ß4galT-7) only 50% of the decorin core protein molecules are substituted with glycosaminoglycan chains. We expressed decorin, as well as wild-type and mutant alleles of ß4galT-7 in galactosyltransferase-deficient CHO618 cells. Decorin was less efficiently substituted with glycosaminoglycan chains upon expression of ß4galT-7186D compared to ß4galT-7-expressing cells. Decorin from ß4galT-7-expressing cells displayed increased molecular heterogeneity. Decorin glycosaminoglycan chains were completely susceptible to chondroitinase ABC treatment. Cells expressing ß4galT-7206P did not synthesize the proteoglycan form of decorin. Thus, the ß4galT-7 mutations directly affect the molecular phenotype of decorin observed in a patient with the progeroid form of Ehlers-Danlos syndrome, which may be a major mechanistic cause for the skin and wound healing defects observed in this patient.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Almeida, R., Levery, S. B., Mandel, U., Kresse, H., Schwientek, T., Bennett, E. P., and Clausen, H. (1999). Cloning and expression of a proteoglycan UDP-galactose:beta-xylose beta1,4-galactosyltransferase I. A seventh member of the human beta4-galactosyltransferase gene family. J. Biol. Chem. 274:26165.
Amado, M., Almeida, R., Schwientek, T., and Clausen, H. (1999). Identification and characterization of large galactosyltransferase gene families: Galactosyltransferases for all functions. Biochim. Biophys. Acta 1473:35.
Bernfield, M., Götte, M., Park, P. W., Reizes, O., Fitzgerald, M. L., Lincecum, J., and Zako, M. (1999). Functions of cell surface heparan sulfate proteoglycans. Annu. Rev. Biochem. 68:729.
Bonner, W. M., and Laskey, R. A. (1974). A film detection method for tritium-labelled proteins and nucleic acids in polyacrylamide gels. Eur. J. Biochem. 46:83.
Breuer, B., Quentin, E., Cully, Z., Götte, M., and Kresse, H. (1991). A novel large dermatan sulfate proteoglycan from human fibroblasts. J. Biol. Chem. 266:13224.
Burch, G. H., Gong, Y., Liu, W., Dettman, R. W., Curry, C. J., Smith, L., Miller, W. L., and Bristow, J. (1997). Tenascin-X deficiency is associated with Ehlers-Danlos syndrome. Nat. Genet. 17:104.
Danielson, K. G., Baribault, H., Holmes, D. F., Graham, H., Kadler, K. E., and Iozzo, R. V. (1997). Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J. Cell Biol. 136:729.
Esko, J. D., Weinke, J. L., Taylor, W. H., Ekborg, G., Rodén, L., Anantharamaiah, G., and Gawish, A. (1987). Inhibition of chondroitin and heparan sulfate biosynthesis in Chinese hamster ovary cell mutants defective in galactosyltransferase I. J. Biol. Chem. 262:12189.
Glössl, J., Beck, M., and Kresse, H. (1984). Biosynthesis of proteodermatan sulfate in cultured human fibroblasts. J. Biol. Chem. 259:1414.
Götte, M. (2003). Syndecans in inflammation. FASEB J. 17:575.
Götte, M., and Fischer von Mollard, G. (1998). A new beat for the SNARE drum. Trends Cell Biol. 8:215.
Götte, M., Joussen, A. M., Klein, C., André, P., Wagner, D. D., Hinkes, M. T., Kirchhof, B., Adamis, A. P., and Bernfield, M. (2002). Role of syndecan-1 in leukocyte-endothelial interactions in the ocular vasculature. Invest. Ophthalmol. Vis. Sci. 43:1135.
Götte, M., Kresse, H., and Hausser, H. (1995). Endocytosis of decorin by bovine aortic endothelial cells. Eur. J. Cell Biol. 166:226.
Grant, D. S., Yenisey, C., Rose, R. W., Tootell, M., Santra, M., and Iozzo, R. V. (2002). Decorin suppresses tumor cell-mediated angiogenesis. Oncogene 21:4765.
Hasilik, A., and Neufeld, E. F. (1980). Biosynthesis of lysosomal enzymes in fibroblasts. Synthesis as precursors of higher molecular weight. J. Biol. Chem. 255:4937.
Hausser, H., and Kresse, H. (1999). Decorin endocytosis: Structural features of heparin and heparan sulphate oligosaccharides interfering with receptor binding and endocytosis. Biochem. J. 344:827.
Iozzo, R. V. (1998). Matrix proteoglycans: From molecular design to cellular function. Annu. Rev Biochem. 67:609.
Kresse, H., Hausser, H., and Schönherr, E. (1993). Small proteoglycans. Experientia 49:403.
Kresse, H., Liszio, C., Schönherr, E., and Fisher, L. W. (1997). Critical role of glutamate in a central leucine-rich repeat of decorin for interaction with type I collagen. J. Biol. Chem. 272:18404.
Kresse, H., Rosthoj, S., Quentin, E., Hollmann, J., Glössl, J., Okada, S., and Tonnesen, T. (1987). Glycosaminoglycan-free small proteoglycan core protein is secreted by fibroblasts from a patient with a syndrome resembling progeroid. Am. J. Hum. Genet. 41:436.
Kresse, H., Seidler F. G. Müller, M., Breuer E., Hausser H., Roughley P. J. and Schönherr, E. (2001). Different usage of the glycosaminoglycan attachment sites of biglycan. J. Biol. Chem. 276:1341.
Lee, J., Sundaram, S., Shaper, N. L., Raju, T. S., and Stanley, P. (2001). Chinese hamster ovary (CHO) cells may express six beta 4-galactosyltransferases (beta 4GalTs). Consequences of the loss of functional beta 4GalT-1, beta 4GalT-6, or both in CHO glycosylation mutants. J. Biol. Chem. 276:13924.
Nakamura, Y., Haines, N., Chen, J., Okajima, T., Furukawa, K., Urano, T., Stanley, P., Irvine, K. D., and Furukawa, K. (2002). Identification of a Drosophila gene encoding xylosylprotein beta4-galactosyltransferase that is essential for the synthesis of glycosaminoglycans and for morphogenesis. J. Biol. Chem. 277:46280.
Okajima, T., Fukumoto, S., Furukawa, K., and Urano, T. (1999). Molecular basis for the progeroid variant of Ehlers-Danlos syndrome. Identification and characterization of two mutations in galactosyltransferase I gene. J. Biol. Chem. 274:28841.
Olguin, H., and Brandan, E. (2002). Decorin is required to maintain commited skeletal muscle cell population grouped allowing normal differentiation in vivo. Mol. Biol. Cell 13S:1918.
Quentin, E., Gladen, A., Rodén, L., and Kresse, H. (1990). A genetic defect in the biosynthesis of dermatan sulfate proteoglycan: Galactosyltransferase I deficiency in fibroblasts from a patient with a progeroid syndrome. Proc. Natl. Acad. Sci. U.S.A. 87:1342.
Quentin-Hoffmann, E., Harrach, B., Robenek, H., and Kresse, H. (1993). Genetic defects in proteoglycan biosynthesis. Paediatr. Paedol. 28:37.
Reed, C. C., Gauldie, J., and Iozzo, R. V. (2002). Suppression of tumorigenicity by adenovirus-mediated gene transfer of decorin. Oncogene 21:3688.
Sambrook, J., Fritsch, E. F., and Maniatis, T. (1989). Molecular Cloning: A Laboratory Manual, 2nd edn., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
Schaefer, L., Macakova, K., Raslik, I., Micegova, M., Gröne, H. J., Schönherr, E., Robenek, H., Echtermeyer, F. G., Grässel, S., Bruckner, P., Schaefer, R. M., Iozzo, R. V., and Kresse, H. (2002). Absence of decorin adversely influences tubulointerstitial fibrosis of the obstructed kidney by enhanced apoptosis and increased inflammatory reaction. Am. J. Pathol. 160:1181.
Sofeu Feugaing, D. D., Götte, M., De La Motte, C., Drazba, J., and Kresse, H. (2002). Involvement of different uptake routes in decorin endocytosis. Mol. Biol. Cell 13S:1919.
Trowbridge, J. M., and Gallo, R. L. (2002). Dermatan sulfate: New functions from an old glycosaminoglycan. Glycobiology 12:117R.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Götte, M., Kresse, H. Defective Glycosaminoglycan Substitution of Decorin in a Patient With Progeroid Syndrome Is a Direct Consequence of Two Point Mutations in the Galactosyltransferase I (ß4galT-7) Gene. Biochem Genet 43, 65–77 (2005). https://doi.org/10.1007/s10528-005-1068-2
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10528-005-1068-2