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J. Biol. Chem., Vol. 279, Issue 31, 32134-32141, July 30, 2004

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Embryonic Fibroblasts with a Gene Trap Mutation in Ext1 Produce Short Heparan Sulfate Chains^*

Shuhei Yamada, Marta Busse, Momoyo Ueno¶, Olivia G. Kelly||, William C. Skarnes||, Kazuyuki Sugahara¶, and Marion Kusche-Gullberg**

From the Department of Medical Biochemistry and Microbiology, Uppsala University, Biomedical Center, P.O. Box 582, SE-751 23 Uppsala, Sweden, the ^¶Department of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan, and the ^||Department of Molecular and Cell Biology, University of California, Berkeley, California 94720

Mutational defects in either EXT1 or EXT2 genes cause multiple exostoses, an autosomal hereditary human disorder. The EXT1 and EXT2 genes encode glycosyltransferases that play an essential role in heparan sulfate chain elongation. In this study, we have analyzed heparan sulfate synthesized by primary fibroblast cell cultures established from mice with a gene trap mutation in Ext1. The gene trap mutation results in embryonic lethality, and homozygous mice die around embryonic day 14. Metabolic labeling and immunohistochemistry revealed that Ext1 mutant fibroblasts still produced small amounts of heparan sulfate. The domain structure of the mutant heparan sulfate was conserved, and the disaccharide composition was similar to that of wild type heparan sulfate. However, a dramatic difference was seen in the polysaccharide chain length. The average molecular sizes of the heparan sulfate chains from wild type and Ext1 mutant embryonic fibroblasts were estimated to be around 70 and 20 kDa, respectively. These data suggest that not only the sulfation pattern but also the length of the heparan sulfate chains is a critical determinant of normal mouse development.

Received for publication, November 19, 2003 , and in revised form, April 14, 2004.

^* This work was supported by Swedish Medical Research Council, Konung Gustav V 80-års Fond Grant 13401, the Human Frontier Science Program, Polysackaridforskning AB (Uppsala, Sweden), the Science Research Promotion Fund from the Japan Private School Promotion Foundation, and Grants-in-aid for Encouragement of Young Scientists 15790056 (to S. Y.) and Scientific Research on Priority Areas 14082207 (to K. S.) from the Ministry of Education, Science, Culture, and Sports of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan.

^** To whom correspondence should be addressed: Dept. of Medical Biochemistry and Microbiology, Uppsala University, Biomedical Center, P.O. Box 582, SE-751 23 Uppsala, Sweden. E-mail: Marion.Kusche{at}imbim.uu.se.

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