caa a22 4500 397573316 CHVBK 20180308164847.0 cr unu---uuuuu 161202e199606 xx s 000 0 eng 10.1093/hmg/5.6.711 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.6.711 Targeted Disruption of the Mouse Sphingolipid Activator Protein Gene: A Complex Phenotype, Including Severe Leukodystrophy and Wide-Spread Storage of Multiple Sphingolipids [Elektronische Daten] [Nobuya Fujita, Kinuko Suzuki, Marie T. Vanier, Brian Popko, Nobuyo Maeda, Andreas Klein, Margarete Henseler, Konrad Sandhoff, Hiroyuki Nakayasu, Kunihiko 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. © 1996 Oxford University Press Fujita Nobuya Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut Suzuki Kinuko Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut Vanier Marie T. INSERM-CNRS 189, Lyon-Sud School of Medicine and Fondation Gillet-Mérieux, Lyon-Sud Hospital, F-69921 Oullins Cedex, France aut Popko Brian Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut Maeda Nobuyo Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut Klein Andreas Institut für Organische Chemie und Biochemie, Universität Bonn, D-53121 Bonn, Germany aut Henseler Margarete Institut für Organische Chemie und Biochemie, Universität Bonn, D-53121 Bonn, Germany aut Sandhoff Konrad Institut für Organische Chemie und Biochemie, Universität Bonn, D-53121 Bonn, Germany aut Nakayasu Hiroyuki Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut Suzuki Kunihiko Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut Human Molecular Genetics Oxford University Press 5/6(1996-06), 711-725 0964-6906 5:6<711 1996 5 hmg https://doi.org/10.1093/hmg/5.6.711 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.6.711 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Fujita Nobuya Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut NATIONALLICENCE 700 1- Suzuki Kinuko Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut NATIONALLICENCE 700 1- Vanier Marie T. INSERM-CNRS 189, Lyon-Sud School of Medicine and Fondation Gillet-Mérieux, Lyon-Sud Hospital, F-69921 Oullins Cedex, France aut NATIONALLICENCE 700 1- Popko Brian Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut NATIONALLICENCE 700 1- Maeda Nobuyo Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut NATIONALLICENCE 700 1- Klein Andreas Institut für Organische Chemie und Biochemie, Universität Bonn, D-53121 Bonn, Germany aut NATIONALLICENCE 700 1- Henseler Margarete Institut für Organische Chemie und Biochemie, Universität Bonn, D-53121 Bonn, Germany aut NATIONALLICENCE 700 1- Sandhoff Konrad Institut für Organische Chemie und Biochemie, Universität Bonn, D-53121 Bonn, Germany aut NATIONALLICENCE 700 1- Nakayasu Hiroyuki Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut NATIONALLICENCE 700 1- Suzuki Kunihiko Brain and Development Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/6(1996-06), 711-725 0964-6906 5:6<711 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford