Nature Genetics
14, 348 - 352 (1996)
doi:10.1038/ng1196-348
Mice lacking both subunits of lysosomal  −hexosaminidase display gangliosidosis and mucopolysaccharidosisKazunori Sango1, Michael P. McDonald2, Jacqueline N. Crawley2, Michelle L. Mack1, Cynthia J. Tifft1, 3, Elisa Skop4, Christopher M. Starr4, Alexander Hoffmann5, Konrad Sandhoff5, Kinuko Suzuki6
& Richard L. Proia1, 7
1Section on Biochemical Genetics, Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Building 10, Room 9D-20, National Institutes of Health, 10 Center DRMSC 1810, Bethesda, Maryland 20892-1810, USA
2Section on Behavioral Neuropharmacology, Experimental Therapeutics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA
3Department of Medical Genetics, Children's National Medical Center, Washington, DC 20010, USA
4Glyko, Inc., 81 Digital Drive, Novato, California 94949, USA
5Institut für Oganische Chemie und Biochemie der Universität Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany
6Department of Pathology and Laboratory Medicine, and UNC Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA
7e-mail: proia@fcrfv1.ncifcrf.gov The GM2 gangliosidoses, Tay-Sachs and Sandhoff diseases, are caused by mutations in the HEXA ( -subunit) and HEXB ( -subunit) genes, respectively. Each gene encodes a subunit for the heterodimeric lysosomal enzyme, (-hexosaminidase A (), as well as for the homodimers -hexosaminidase B () and S (). In this study, we have produced mice that have both Hexa and Hexb genes disrupted through interbreeding Tay-Sachs1 (Hexa-/-) and Sandhoff2 (Hexb-/-) disease model mice. Lacking both the and -subunits these 'double knockout' mice displayed a total deficiency of all forms of lysosomal -hexosaminidase including the small amount of -hexosaminidase S present in the Sandhoff disease model mice. More surprisingly, these mice showed the phenotypic, pathologic and biochemical features of the mucopolysaccharidoses, lysosomal storage diseases caused by the accumulation of glycosaminoglycans. The mucopolysaccharidosis phenotype is not seen in the Tay-Sachs or Sandhoff disease model mice or in the corresponding human patients3,4,5. This result demonstrates that glycosaminoglycans are crucial substrates for -hexosaminidase and that their lack of storage in Tay-Sachs and Sandhoff diseases is due to functional redundancy in the -hexosaminidase enzyme system.
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