Targeted Disruption of the Hexa Gene Results in Mice with Biochemical and Pathologic Features of Tay-Sachs Disease

Tay-Sachs disease, the prototype of the GM2gangliosidoses, is a catastrophic neurodegenerative disorder of infancy. The disease is caused by mutations in the HEXA gene resulting in an absence of the lysosomal enzyme, β-hexosaminidase A. As a consequence of the enzyme deficiency, GM2ganglioside accumulates progressively, beginning early in fetal life, to excessive amounts in the central nervous system. Rapid mental and motor deterioration starting in the first year of life leads to death by 2-4 years of age. Through the targeted disruption of the mouse Hexa gene in embryonic stem cells, we have produced mice with biochemical and neuropathologic features of Tay-Sachs disease. The mutant mice displayed