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Originally published In Press as doi:10.1074/jbc.C000847200 on December 27, 2000

J. Biol. Chem., Vol. 276, Issue 10, 6885-6888, March 9, 2001
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ACCELERATED PUBLICATION
Mice Expressing Only Monosialoganglioside GM3 Exhibit Lethal Audiogenic Seizures*

Hiromichi KawaiDagger §, Maria Laura AllendeDagger , Ryuichi WadaDagger , Mari KonoDagger , Kazunori SangoDagger ||, Chuxia DengDagger , Tsuyoshi Miyakawa**Dagger Dagger , Jacqueline N. Crawley**, Norbert Werth§§, Uwe Bierfreund§§¶¶, Konrad Sandhoff§§, and Richard L. ProiaDagger ||||

From the Dagger  Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, ** Section on Behavioral Neuropharmacology, Experimental Therapeutics Branch, National Institute of Mental Health, Bethesda, Maryland 20892, and §§ Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, Gerhard- Domagk-Strasse 1, 53121 Bonn, Germany

Gangliosides are a family of glycosphingolipids that contain sialic acid. Although they are abundant on neuronal cell membranes, their precise functions and importance in the central nervous system (CNS) remain largely undefined. We have disrupted the gene encoding GD3 synthase (GD3S), a sialyltransferase expressed in the CNS that is responsible for the synthesis of b-series gangliosides. GD3S-/- mice, even with an absence of b-series gangliosides, appear to undergo normal development and have a normal life span. To further restrict the expression of gangliosides, the GD3S mutant mice were crossbred with mice carrying a disrupted GalNAcT gene encoding beta 1,4-N-acetylgalactosaminyltransferase. These double mutant mice expressed GM3 as their major ganglioside. In contrast to the single mutant mice, the double mutants displayed a sudden death phenotype and were extremely susceptible to induction of lethal seizures by sound stimulus. These results demonstrate unequivocally that gangliosides play an essential role in the proper functioning of the CNS.

* This work was supported in part by funding from the Deutsche Forschungsgemeinschaft (SFB 284 to K. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Third Dept. of Medicine, Shiga University of Medical Science, Otsu 520-2192, Japan.

Present address: Dept. of Pathology, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan.

|| Present address: Dept. of Developmental Morphology, Tokyo Metropolitan Institute for Neuroscience, Tokyo 183-8526, Japan.

Dagger Dagger Present address: Dept. of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6600.

¶¶ Present address: Biacore AB, Königsheide 28, D-44536 Lünen, Germany.

|||| To whom correspondence should be addressed: Bldg. 10, Rm. 9N-314, National Institutes of Health, Bethesda, MD 20892-1821.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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