Human Molecular Genetics Advance Access published online on September 2, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh281
© 2004 by Oxford University Press
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Pediatrics, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan
* To whom correspondence should be addressed. E-mail: junko{at}clin.med.tokushima-u.ac.jp.
The sphingolipid activator proteins (saposins A, B, C, D) are small homologous glycoproteins that are encoded by a single gene in tandem within a large precursor protein (prosaposin) and are required for in vivo degradation of some sphingolipids with relatively short carbohydrate chains. Human patients with prosaposin or specific saposin B or C deficiency are known, and prosaposin- and saposin A-deficient mouse lines have been generated. Experimental evidence suggests that saposin D may be a lysosomal acid ceramidase activator. However, no specific saposin D deficiency state is known in any mammalian species. We have generated a specific saposin D-/- mouse by introducing a mutation (C509S) into the saposin D domain of the mouse prosaposin gene. Saposin D-/- mice developed progressive polyuria at around 2 months and ataxia at around 4 months. Pathologically, the kidney of saposin D-/- mice showed renal tubular degeneration and eventual hydronephrosis. In the nervous system, progressive and selective loss of the cerebellar Purkinje cells in a striped pattern was conspicuous, and almost all Purkinje cells disappeared by 12 months. Biochemically, ceramides, particularly those containing hydroxy fatty acids accumulated in the kidney and the brain, most prominently in the cerebellum. These results not only indicate the role of saposin D in in vivo ceramide metabolism but also suggest possible cytotoxicity of ceramide underlying the cerebellar Purkinje cell and renal tubular cell degeneration.
Article
Mutation in saposin D domain of sphingolipid activator protein gene causes urinary system defects and cerebellar Purkinje cell degeneration with accumulation of hydroxy fatty acid-containing ceramide in the mouse
2 Department of Biochemistry, Teikyo University School of Medicine, Kaga 2-11-1, Itabashi-ku, Tokyo 173-8605, Japan
3 Department of Anatomy and Cell Biology, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan
4 Department of Clinical Neutrition, The Institute of Health Bioscience, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan
5 Neuroscience Center, Departments of Neurology and Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-7250, USA; Institute of Glycotechnology, Future Science & Technology Joint Research Center, Tokai University, Hiratsuka 259-1292, Japan
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  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. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kyogashima, K. Tadano-Aritomi, T. Aoyama, A. Yusa, Y. Goto, K. Tamiya-Koizumi, H. Ito, T. Murate, R. Kannagi, and A. Hara Chemical and Apoptotic Properties of Hydroxy-Ceramides Containing Long-Chain Bases with Unusual Alkyl Chain Lengths J. Biochem., July 1, 2008; 144(1): 95 - 106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun, D. P. Witte, M. Zamzow, H. Ran, B. Quinn, J. Matsuda, and G. A. Grabowski Combined saposin C and D deficiencies in mice lead to a neuronopathic phenotype, glucosylceramide and {alpha}-hydroxy ceramide accumulation, and altered prosaposin trafficking Hum. Mol. Genet., April 15, 2007; 16(8): 957 - 971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Yuan, X. Qi, P. Tsang, S.-J. Kang, P. A. Illarionov, G. S. Besra, J. Gumperz, and P. Cresswell Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules PNAS, March 27, 2007; 104(13): 5551 - 5556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Akil, J. Chang, H. Hiel, J.-H. Kong, E. Yi, E. Glowatzki, and L. R. Lustig Progressive Deafness and Altered Cochlear Innervation in Knock-Out Mice Lacking Prosaposin J. Neurosci., December 13, 2006; 26(50): 13076 - 13088. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Locatelli-Hoops, N. Remmel, R. Klingenstein, B. Breiden, M. Rossocha, M. Schoeniger, C. Koenigs, W. Saenger, and K. Sandhoff Saposin A Mobilizes Lipids from Low Cholesterol and High Bis(monoacylglycerol)phosphate-containing Membranes: PATIENT VARIANT SAPOSIN A LACKS LIPID EXTRACTION CAPACITY J. Biol. Chem., October 27, 2006; 281(43): 32451 - 32460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Langmade, S. E. Gale, A. Frolov, I. Mohri, K. Suzuki, S. H. Mellon, S. U. Walkley, D. F. Covey, J. E. Schaffer, and D. S. Ory Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann-Pick C disease PNAS, September 12, 2006; 103(37): 13807 - 13812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kolter, F. Winau, U. E. Schaible, M. Leippe, and K. Sandhoff Lipid-binding Proteins in Membrane Digestion, Antigen Presentation, and Antimicrobial Defense J. Biol. Chem., December 16, 2005; 280(50): 41125 - 41128. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Cohen, W. Auerbach, L. Ravid, J. Bodennec, A. Fein, A. H. Futerman, A. L. Joyner, and M. Horowitz The Exon 8-Containing Prosaposin Gene Splice Variant Is Dispensable for Mouse Development, Lysosomal Function, and Secretion Mol. Cell. Biol., March 15, 2005; 25(6): 2431 - 2440. [Abstract] [Full Text] [PDF]
|
|