TARGETED DISRUPTION OF THE HEXA GENE RESULTS IN MICE WITH BIOCHEMICALAND PATHOLOGICAL FEATURES OF TAY-SACHS-DISEASE

Tay-Sachs disease, the prototype of the G(M2) gangliosidoses, is a cat astrophic neurodegenerative disorder of infancy. The disease is caused by mutations in the HEXA gene resulting in an absence of the lysosoma l enzyme, beta-hexosaminidase A. As a consequence of the enzyme defici ency, G(M2) ganglioside 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 lead s 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 b iochemical and neuropathologic features of Tay-Sachs disease. The muta nt mice displayed <1% of normal beta-hexosaminidase A activity and acc umulated G(M2) ganglioside in their central nervous system in an age-d ependent manner. The accumulated ganglioside was stored in neurons as membranous cytoplasmic bodies characteristically found in the neurons of Tay-Sachs disease patients. At 3-5 months of age, the mutant mice s howed no apparent defects in motor or memory function. These beta-hexo saminidase A deficient mice should be useful for devising strategies t o introduce functional enzyme and genes into the central nervous syste m. This model may also be valuable for studying the biochemical and pa thologic changes occurring during the course of the disease.