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Human Molecular Genetics Advance Access published online on March 12, 2007
Human Molecular Genetics, 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 Sun1,4, David P. Witte2,5, Matt Zamzow1,4, Huimin Ran1,4, Brian Quinn1,4, Junko Matsuda3 and Gregory A. Grabowski1,4,*

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

Correspondence to: Gregory A. Grabowski, M.D. Cincinnati Children's Hospital Medical Center Division of Human Genetics 3333 Burnet Avenue Cincinnati, Ohio 45229-3039 Phone: (513) 636-7290 Fax: (513) 636-2261 E-mail address: greg.grabowski{at}cchmc.org

Received January 29, 2007; Revised February 16, 2007; Accepted February 21, 2007

Saposins (A, B, C and D) are ~80 amino acid stimulators of glycosphingolipid 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 to 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 glycosphingolipid 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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