title: An inducible mouse model of late onset Tay-Sachs disease.
abstract: 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.
authors.affiliation: Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: Mylvaganam
authors.initials: M
authors.lastname: Jeyakumar
authors.forename: David
authors.initials: D
authors.lastname: Smith
authors.forename: Elena
authors.initials: E
authors.lastname: Eliott-Smith
authors.forename: Mario
authors.initials: M
authors.lastname: Cortina-Borja
authors.forename: Gabriele
authors.initials: G
authors.lastname: Reinkensmeier
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lemm
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
authors.forename: V Hugh
authors.initials: VH
authors.lastname: Perry
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
mesh_terms: 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
chemical_list: D005678:G(M2) Ganglioside