Human Molecular Genetics, 2001, Vol. 10, No. 11 1191-1199
© 2001 Oxford University Press
A mutation in the saposin A domain of the sphingolipid activator protein (prosaposin) gene results in a late-onset, chronic form of globoid cell leukodystrophy in the mouse
1Neuroscience Center, 2Departments of Neurology and Psychiatry and 3Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7250, USA and 4INSERM U 189, Lyon-Sud School of Medicine and Fondation Gillet-Mérieux, Lyon-Sud Hospital, 69921 Oullins Cedex, France
Sphingolipid activator proteins (saposins A, B, C and D) are small homologous glycoproteins derived from a common precursor protein (prosaposin) encoded by a single gene. They are required for in vivo degradation of sphingolipids with short carbohydrate chains. Six cysteines and one glycosylation site are strictly conserved in all four saposins. Total deficiency of all saposins and specific deficiency of saposin B or C are known among human patients. A mouse model of total saposin deficiency closely mimics the human disease. However, no specific saposin A or D deficiency is known. We introduced an amino acid substitution (C106F) into the saposin A domain by the Cre/loxP system which eliminated one of the three conserved disulfide bonds. Saposin A–/– mice developed slowly progressive hind leg paralysis with clinical onset at 
2.5 months and survival up to 5 months. Tremors and shaking, prominent in other myelin mutants, were not obvious until the terminal stage. Pathology and analytical biochemistry were qualitatively identical to, but generally much milder than, that seen in the typical infantile globoid cell leukodystrophy (GLD) in man (Krabbe disease) and in several other mammalian species, due to genetic deficiency of lysosomal galactosylceramidase (GALC) (EC 3.2.1.46). Thus, saposin A is indispensable for in vivo degradation of galactosylceramide by GALC. It should now be recognized that, in addition to GALC deficiency, genetic saposin A deficiency could also cause chronic GLD. Genetic saposin A deficiency might be anticipated among human patients with undiagnosed late-onset chronic leukodystrophy without GALC deficiency.
+ Present address: Nishi-Niigata Central Hospital, 1-14-1 Masago, Niigata 950-2085, Japan
To whom correspondence should be addressed at: Neuroscience Center, CB#7250, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7250, USA. Tel: +1 919 966 2405; Fax: +1 919 966 1322; Email: kuni.suzuki@attglobal.net
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