title: Characterization of a C57BL/6 congenic mouse strain of mucopolysaccharidosis type IIIA.
abstract: The original mucopolysaccharidosis type IIIA (MPS IIIA) mice were identified in a mixed background with contributions from four different strains. To ensure long-term stability and genetic homogeneity of this lysosomal storage disease (LSD) model, the aim of this study was to develop and characterize a C57BL/6 congenic strain. The B6.Cg-Sgsh(mps3a) strain compares favorably with the original mixed donor strain, exhibiting low liver sulfamidase activity and significant brain heparan sulfate-derived disaccharide elevation from birth. A rapid increase in brain disaccharide levels occurred after birth, with a plateau reached by 13 weeks of age at 110x the levels observed in brains of age-matched unaffected mice. Typical lysosomal inclusions were observed in cerebral cortical and cerebellar neurons and in liver hepatocytes and Kupffer cells. Ubiquitin-positive spheroids and GM(2)-ganglioside were also detected in brain. Using the Morris water maze in male mice, impaired memory and spatial learning was evident at 20 weeks of age in B6.Cg-Sgsh(mps3a) MPS IIIA mice. Other behavioral changes include motor, cognitive and sensory deficits, and aggression. Male B6.Cg-Sgsh(mps3a) MPS IIIA mice exhibited more behavioral abnormalities than B6.Cg-Sgsh(mps3a) MPS IIIA females, as observed previously in the original mixed background strain. Affected mice generally survive to 9 to 12 months of age, before death or euthanasia for humane reasons. Overall, minor differences were apparent between the new congenic and previously described mixed MPS IIIA strains. Availability of an in-bred strain will ensure more reproducible experimental outcomes thereby assisting in our goal of developing effective therapies for LSD with central nervous system disease.
authors.affiliation: Lysosomal Diseases Research Unit, Department of Genetic Medicine, Children, Youth and Women's Health Service, 72 King William Road, North Adelaide, SA 5006, South Australia. allisom.crawley@adelaide.edu.au
authors.forename: Allison C
authors.initials: AC
authors.lastname: Crawley
authors.forename: Briony L
authors.initials: BL
authors.lastname: Gliddon
authors.forename: Dyane
authors.initials: D
authors.lastname: Auclair
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Brodie
authors.forename: Craig
authors.initials: C
authors.lastname: Hirte
authors.forename: Barbara M
authors.initials: BM
authors.lastname: King
authors.forename: Maria
authors.initials: M
authors.lastname: Fuller
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hemsley
authors.forename: John J
authors.initials: JJ
authors.lastname: Hopwood
mesh_terms: D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001947:Breeding / Q000379:methods; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005678:G(M2) Ganglioside / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006867:Hydrolases / Q000172:deficiency*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009084:Mucopolysaccharidosis III / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D012737:Sex Factors; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D005678:G(M2) Ganglioside; D006867:Hydrolases; C022708:N-sulfoglucosamine sulfohydrolase