An inducible mouse model of late onset Tay-Sachs disease.
Mouse models of the G(M2) gangliosidoses, Tay-Sachs and Sandhoff disease, are null for the hexosaminidase alpha and beta 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 approximately 65% 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.
Jeyakumar
Mylvaganam
M
Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
Smith
David
D
Eliott-Smith
Elena
E
Cortina-Borja
Mario
M
Reinkensmeier
Gabriele
G
Butters
Terry D
TD
Lemm
Thorsten
T
Sandhoff
Konrad
K
Perry
V Hugh
VH
Dwek
Raymond A
RA
Platt
Frances M
FM
D017668:Age of Onset; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005678:G(M2) Ganglioside / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D011247:Pregnancy; D013661:Tay-Sachs Disease / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology
D005678:G(M2) Ganglioside