Targeted disruption of the Hexa gene results in mice with biochemical and pathologic features of Tay-Sachs disease

Shoji Yamanaka, Mark D. Johnson, Alex Grinberg, Heiner Westphal, Jacqueline Crawley, Masako Taniike, Kinuko Suzuki, Richard L. Proia

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

Tay-Sachs disease, the prototype of the G(M2) gangliosidoses, 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, 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 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 <1% of normal β- hexosaminidase A activity and accumulated G(M2) ganglioside in their central nervous system in an age-dependent 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 showed no apparent defects in motor or memory function. These β- hexosaminidase A-deficient mice should be useful for devising strategies to introduce functional enzyme and genes into the central nervous system. This model may also be valuable for studying the biochemical and pathologic changes occurring during the course of the disease.

Original languageEnglish (US)
Pages (from-to)9975-9979
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number21
DOIs
StatePublished - Oct 11 1994
Externally publishedYes

Keywords

  • animal model
  • G(M2) gangliosidosis
  • homologous recombination
  • lysosomal storage disease

ASJC Scopus subject areas

  • Genetics
  • General

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