Human Molecular Genetics, Vol 5, 711-725, Copyright © 1996 by Oxford University Press
N Fujita, K Suzuki, MT Vanier, B Popko, N Maeda, A Klein, M Henseler, K Sandhoff, H Nakayasu and K Suzuki
The four established or putative sphingolipid activator proteins derive
from a large precursor protein encoded by a single gene. In addition to
generating the four sphingolipid activator proteins, the precursor protein
is suspected of having functions of its own, as, for example, a lipid
binding/transport protein or a neurotrophic factor. The gene also appears
to encode the Sertoli cell major sulfated glycoprotein. Sequence
similarities have been noted with many other proteins of diverse functions.
One patient and a fetus in a single family with a complete defect of this
gene due to a mutation in the initiation codon exhibited complex
pathological and biochemical abnormalities. Mutant mice homozygous for an
inactivated gene of the sphingolipid activator protein precursor exhibit
two distinct clinical phenotypes-neonatally fatal and later-onset. The
latter develop rapidly progressive neurological signs around 20 days and
die by 35-38 days. At 30 days, severe hypomyelination and periodic
acid-Schiff-positive materials throughout the nervous system and in
abnormal cells in the liver and spleen are the main pathology. Most
prominently lactosylceramide, and additionally ceramide, glucosylceramide,
galactosylceramide, sulfatide, and globotriaosylceramide are abnormally
increased in the brain, liver, kidney, and their catabolism abnormally slow
in cultured fibroblasts. Brain gangliosides are generally increased,
particularly the monosialogangliosides. The clinical, pathological and
biochemical phenotype closely resembles that of the human disease. This
model not only allows further clarification of the physiological functions
of the four individual sphingolipid activator proteins but also should be
useful to explore putative functions of the precursor protein.
ARTICLES
Targeted disruption of the mouse sphingolipid activator protein gene: a complex phenotype, including severe leukodystrophy and wide-spread storage of multiple sphingolipids
Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill 27599, USA.
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