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Mucopolysaccharidosis Type IIIB and GalNAc Transferase Double Knockout Mice Manifest Early Onset Fatal Leukodystrophy
Author(s) -
Whitley Elizabeth M.,
Snella Elizabeth M.,
Dierenfeld Ashley D.,
Echevarria Franklin D.,
Ellinwood N. Matthew
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.568.3
Subject(s) - ataxia , white matter , knockout mouse , vacuolization , pathology , arylsulfatase a , medicine , mucopolysaccharidosis , leukoencephalopathy , endocrinology , chemistry , biology , neuroscience , metachromatic leukodystrophy , disease , receptor , magnetic resonance imaging , radiology
Mucopolysaccharidosis type IIIB (MPS IIIB) causes progressive mental degeneration and early death due to lysosomal accumulation of heparan sulfate resulting from deficient activity of N‐acetyl‐α‐D‐glucosaminidase. Lysosomal accumulation of GM2 and GM3 gangliosides by unknown mechanism also occurs. We tested the benefit of eliminating GM2 storage in MPS III, by breeding MPS IIIB/GalNAc transferase double knockout (KO) mice. Rather than an improved outcome, double KO mice were short lived (p < 0.0001); 20 ± 3.4 wks, versus 45 ± 6.9 wks (MPS IIIB). Double KO mice had hind limb ataxia and hyper‐extension in contrast to single KO or normal mice, which appeared normal. Brain tissue of MPS IIIB‐affected, GalNAcT deficient, double KO, or wild‐type mice was examined histologically. In double KO mice, white matter showed prominent vacuolization and degeneration of nerve fibers. In contrast, MPS IIIB mice showed only intracytoplasmic vacuoles of many neurons and glia. Double KO mice likely succumbed to axonopathic and neuropathic effects in white matter tracts. This double KO model may prove useful as an improved model to investigate neuropathology and to assess therapy for MPS IIIB. Funded by the Sanfilippo Children's Research Foundation, the Lysosomal Storage Disease Research Consortium, the Center for Integrated Animal Genomics at ISU, and the State of Iowa Board of Regents.