Nature Genetics
11, 170 - 176 (1995)
doi:10.1038/ng1095-170
Mouse models of Tay−Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolismKazunori Sango1, Shoji Yamanaka1, 6, Alexander Hoffmann2, Yasuharu Okuda1, Alexander Grinberg3, Heiner Westphal3, Michael P. McDonald4, Jacqueline N. Crawley4, Konrad Sandhoff2, Kinuko Suzuki5
& Richard L. Proia1
1Section on Biochemical Genetics, Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA
2Institut für Oganische Chemie und Biochemie der Universität Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
3Laboratory of Mammalian Genes and Development, National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland, 20892, USA
4Section on Behavioral Neuropharmacology, Experimental Therapeutics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, 20892, USA
5Department of Pathology, and Brain and Development Research Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA
6Present address: Department of Pathology, Yokohama City University, School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236, Japan Correpsondence should be addressed to R.L.P. Tay−Sachs and Sandhoff diseases are clinically similar neurodegenerative disorders. These two sphingolipidoses are characterized by a heritable absence of  −hexosaminidase A resulting in defective GM2 ganglioside degradation. Through disruption of the Hexa and Hexb genes in embryonic stem cells, we have established mouse models corresponding to each disease. Unlike the two human disorders, the two mouse models show very different neurologic phenotypes. Although exhibiting biochemical and pathologic features of the disease, the Tay−Sachs model showed no neurological abnormalities. In contrast, the Sandhoff model was severely affected. The phenotypic difference between the two mouse models is the result of differences in the ganglioside degradation pathway between mice and humans.
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