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Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases.

We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption of the Hexa (alpha subunit) or Hexb (beta subunit) genes, respectively, encoding lysosomal beta-hexosaminidase A (structure, alpha) and B (structure, beta beta). Both mutant mice accumulate GM2 ganglioside in brain, much more so in Hexb -/- mice, and the latter also accumulate glycolipid GA2. Hexa -/- mice suffer no obvious behavioral or neurological deficit, while Hexb -/- mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia. The Hexb -/- but not the Hexa -/- mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of GM2. We propose that Hexa -/- mice escape disease through partial catabolism of accumulated GM2 via GA2 (asialo-GM2) through the combined action of sialidase and beta-hexosaminidase B.

Pubmed ID: 8789434


  • Phaneuf D
  • Wakamatsu N
  • Huang JQ
  • Borowski A
  • Peterson AC
  • Fortunato SR
  • Ritter G
  • Igdoura SA
  • Morales CR
  • Benoit G
  • Akerman BR
  • Leclerc D
  • Hanai N
  • Marth JD
  • Trasler JM
  • Gravel RA


Human molecular genetics

Publication Data

January 22, 1996

Associated Grants


Mesh Terms

  • Animals
  • Base Sequence
  • Brain Chemistry
  • Brain Injuries
  • Disease Models, Animal
  • Female
  • G(M2) Ganglioside
  • Gene Targeting
  • Glycosphingolipids
  • Hexosaminidase A
  • Hexosaminidase B
  • Humans
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Organ Specificity
  • Phenotype
  • RNA, Messenger
  • Sandhoff Disease
  • Spinal Cord
  • Tay-Sachs Disease
  • beta-N-Acetylhexosaminidases