Jeyakumar, Mylvaganam, Smith, David, Eliott-Smith, Elena, Cortina-Borja, Mario, Reinkensmeier, Gabriele, Butters, Terry D., Lemm, Thorsten, Sandhoff, Konrad, Perry, V. Hugh, Dwek, Raymond A. and Platt, Frances M.
An inducible mouse model of late onset Tay-Sachs disease.
Neurobiology of Disease, 10, (3), . (doi:10.1006/nbdi.2002.0511).
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Mouse models of the GM2 gangliosidoses, Tay–Sachs and Sandhoff disease, are null for the hexosaminidase ? and ? subunits respectively. The Sandhoff (Hexb?/?) mouse has severe neurological disease and mimics the human infantile onset variant. However, the Tay–Sachs (Hexa?/?) mouse model lacks an overt phenotype as mice can partially bypass the blocked catabolic pathway and escape disease. We have investigated whether a subset of Tay–Sachs mice develop late onset disease. We have found that not, vert, similar65% of the mice develop one or more clinical signs of the disease within their natural life span (n = 52, P < 0.0001). However, 100% of female mice with repeat breeding histories developed late onset disease at an earlier age (n = 21, P < 0.0001) and displayed all clinical features. Repeat breeding of a large cohort of female Tay–Sachs mice confirmed that pregnancy induces late onset Tay–Sachs disease. Onset of symptoms correlated with reduced up-regulation of hexosaminidase B, a component of the bypass pathway.
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