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Human Molecular Genetics Advance Access originally published online on March 12, 2007
Human Molecular Genetics 2007 16(8):957-971; doi:10.1093/hmg/ddm040
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Combined saposin C and D deficiencies in mice lead to a neuronopathic phenotype, glucosylceramide and {alpha}-hydroxy ceramide accumulation, and altered prosaposin trafficking

Ying Sun1,3, David P. Witte2,4, Matt Zamzow1,3, Huimin Ran1,3, Brian Quinn1,3, Junko Matsuda5 and Gregory A. Grabowski1,3,*

1 Division of Human Genetics, 2 Division of Pediatric Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, 3 Department of Pediatrics, 4 Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH 45229 3039, USA and 5 Institute of Glycotechnology, Tokai University, Kanagawa, Japan

* To whom correspondence should be addressed at: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229 3039, USA. Tel: +1 5136367290; Fax: +1 5136362261; Email: greg.grabowski{at}cchmc.org

Saposins (A, B, C and D) are ~80 amino acid stimulators of glycosphingolipid (GSL) hydrolases that derive from a single precursor, prosaposin. In both humans and mice, prosaposin/saposin deficiencies lead to severe neurological deficits. The CD–/– mice with saposin C and D combined deficiencies were produced by introducing genomic point mutations into a critical cysteine in each of these saposins. These mice develop a severe neurological phenotype with ataxia, kyphotic posturing and hind limb paralysis. Relative to prosaposin null mice (~30 days), CD–/– mice had an extended life span (~56 days). Loss of Purkinje cells was evident after 6 weeks, and storage bodies were present in neurons of the spinal cord, brain and dorsal root ganglion. Electron microscopy showed well-myelinated fibers and axonal inclusions in the brain and sciatic nerve. Marked accumulations of glucosylceramides and {alpha}-hydroxy ceramides were present in brain and kidney. Minor storage of lactosylceramide (LacCer) was observed when compared with tissues from the prosaposin null mice, suggesting a compensation in LacCer degradation by saposin B for the saposin C deficiency. Skin fibroblasts and tissues from CD–/– mice showed an increase of intracellular prosaposin, impaired prosaposin secretion, deficiencies of saposins C and D and decreases in saposins A and B. In addition, the deficiency of saposin C in CD–/– mice resulted in cellular decreases of acid ß-glucosidase activity and protein. This CD null mouse model provides a tool to explore the in vivo functional interactions of saposins in GSL metabolism and lysosomal storage diseases, and prosaposin's physiological effects.


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Y. Sun, D. P. Witte, H. Ran, M. Zamzow, S. Barnes, H. Cheng, X. Han, M. T. Williams, M. R. Skelton, C. V. Vorhees, et al.
Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice
Hum. Mol. Genet., August 1, 2008; 17(15): 2345 - 2356.
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