title: 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 mouse.
abstract: The sphingolipid activator proteins (saposins A, B, C and 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.
authors.affiliation: Department of Pediatrics, The Institute of Health Bioscience, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan. junko@clin.med.tokushima-u.ac.jp
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuda
authors.forename: Makiko
authors.initials: M
authors.lastname: Kido
authors.forename: Keiko
authors.initials: K
authors.lastname: Tadano-Aritomi
authors.forename: Ineo
authors.initials: I
authors.lastname: Ishizuka
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tominaga
authors.forename: Kazunori
authors.initials: K
authors.lastname: Toida
authors.forename: Eiji
authors.initials: E
authors.lastname: Takeda
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kuroda
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics; D064026:Calbindins; D002518:Ceramides / Q000096:biosynthesis* / Q000737:chemistry; D002540:Cerebral Cortex / Q000166:cytology; D002874:Chromosome Mapping; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009154:Mutation; D011141:Polyuria / Q000209:etiology / Q000235:genetics; D017434:Protein Structure, Tertiary; D011689:Purkinje Cells / Q000473:pathology*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D049231:Saposins / Q000737:chemistry / Q000235:genetics*; D021241:Spectrometry, Mass, Electrospray Ionization; D049128:Sphingolipid Activator Proteins / Q000235:genetics*; D013997:Time Factors; D014018:Tissue Distribution; D014570:Urologic Diseases / Q000235:genetics* / Q000473:pathology
chemical_list: D064026:Calbindins; D002518:Ceramides; D064030:S100 Calcium Binding Protein G; D049231:Saposins; D049128:Sphingolipid Activator Proteins