Human Molecular Genetics, 2000, Vol. 9, No. 11 1699-1707
© 2000 Oxford University Press
Paradoxical influence of acid ß-galactosidase gene dosage on phenotype of the twitcher mouse (genetic galactosylceramidase deficiency)
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 U189, Lyon-Sud School of Medicine and Fondation Gillet-Mérieux, Lyon-Sud Hospital, 69921 Oullins Cedex, France
We have cross-bred twitcher mice (galactosylceramidase deficiency) and acid ß-galactosidase knockout mice (GM1 gangliosidosis) and found that the acid ß-galactosidase gene dosage exerts an unexpected and paradoxical influence on the twitcher phenotype. Twitcher mice with an additional complete deficiency of acid ß-galactosidase have the mildest phenotype with the longest lifespan and nearly rescued CNS pathology. In contrast, twitcher mice with a single functional acid ß-galactosidase gene have the most severe disease with the shortest lifespan, despite the fact that GM1 gangliosidosis carrier mice with an otherwise normal genetic background are phenotypically normal. A significant proportion of these galc–/–, bgal+/– mice clinically develop additional extreme hyper-reactivity and generalized seizures not seen in any other genotypes. Consistent with the clinical seizures, widespread neuronal degeneration is present in the galc–/–, bgal+/– mice, most prominently in the CA3 region of the hippocampus. The double knockout mice show a massive accumulation of lactosylceramide in all tissues. The brain inexplicably contains only a half-normal amount of galactosylceramide, which may account for the mild clinical and pathological phenotype. On the other hand, brain psychosine level is increased in all twitcher mice, but galc–/–, bgal+/– mice show a significantly higher level than other genotypes. The reduced galactosylceramide in the brain of the double knockout mice and the significantly higher psychosine in the brain of the galc–/–, bgal+/– mice cannot readily be explained from the genotypes of these mice. These observations are contrary to the expected outcome of Mendelian autosomal recessive single gene disorders and may also be interpreted as that the acid ß-galactosidase gene functions as a modifier gene for the phenotypic expression of genetic galactosylceramidase deficiency.
+ Present address: National Nishi-Niigata Hospital, Masago, Niigata 950-2085, Japan
§ Present address: Tokyo Metropolitan Higashi-yamato Medical Center for the Handicapped, Higashi-yamato, Tokyo 207-0022, 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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