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.