Mice lacking both subunits of lysosomal β–hexosaminidase display gangliosidosis and mucopolysaccharidosis

The GM2 gangliosidoses, Tay-Sachs and Sandhoff diseases, are caused by mutations in the HEXA (α-subunit) and HEXB (β-subunit) genes, respectively. Each gene encodes a subunit for the heterodimeric lysosomal enzyme, (β-hexosaminidase A (αβ), as well as for the homodimers β-hexosaminidase B (ββ) and S (αα). 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 α and β-subunits these ‘double knockout’ mice displayed a total deficiency of all forms of lysosomal β-hexosaminidase including the small amount of β-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 β-hexosaminidase and that their lack of storage in Tay-Sachs and Sandhoff diseases is due to functional redundancy in the β-hexosaminidase enzyme system.