DISRUPTION OF MURINE HEXA GENE LEADS TO ENZYMATIC DEFICIENCY AND TO NEURONAL LYSOSOMAL STORAGE, SIMILAR TO THAT OBSERVED IN TAY-SACHS-DISEASE

Tay-Sachs disease is an autosomal recessive lysosomal storage disease caused by beta-hexosaminidase A deficiency and leads to death in early childhood. The disease results from mutations in the HEXA gene, which codes for the alpha chain of beta-hexosaminidase. The catastrophic ne urodegenerative progression of the disease is thought to be a conseque nce of massive neuronal accumulation of G(M2) ganglioside and related glycolipids in the brain and nervous system of the patients. Fuller un derstanding of the pathogenesis and the development of therapeutic pro cedures have both suffered from the lack of an animal model. We have u sed gene targeting in embryonic stent (ES) cells to disrupt the mouse Hexa gene. Mice homozygous for the disrupted allele mimic several bioc hemical and histological features of human Tay-Sachs disease. Hexa -/- mice displayed a total deficiency of beta-hexosaminidase A activity, and membranous cytoplasmic inclusions typical of G(M2) gangliosidoses were found in the cytoplasm of their neurons. However, while the numbe r of storage neurons increased with age, it remained low compared with that found in human, and no apparent motor or behavioral disorders co uld be observed. This suggests that the presence of beta-hexosaminidas e A is not an absolute requirement of ganglioside degradation in mice. These mice should help us to understand several aspects of the diseas e as well as the physiological functions of hexosaminidase in mice, Th ey should also provide a valuable animal model in which to test new fo rms of therapy, and in particular gene delivery into the central nervo us system.