title: Case study on the pathophysiology of Fabry disease: abnormalities of cellular membranes can be reversed by substrate reductionin vitro.
abstract: It is still not entirely clear how α-galactosidase A (GAA) deficiency translates into clinical symptoms of Fabry disease (FD). The present communication investigates the effects of the mutation N215S in FD on the trafficking and processing of lysosomal GAA and their potential association with alterations in the membrane lipid composition. Abnormalities in lipid rafts (LRs) were observed in fibroblasts isolated from a male patient with FD bearing the mutation N215S. Interestingly, LR analysis revealed that the distribution of cholesterol and flotillin-2 are distinctly altered in the Fabry fibroblasts when compared with that of the wild-type cells. Furthermore, increased levels of glycolipid globotriaosylceramide 3 (Gb3) and sphingomyelin (SM) were observed in non-raft membrane fractions of Fabry cells. Substrate reduction withN-butyldeoxynojirimycin (NB-DNJ)in vitrowas capable of reversing these abnormalities in this patient. These data led to the hypothesis that alterations of LRs may contribute to the pathophysiology of Morbus Fabry. Furthermore, it may be suggested that substrate reduction therapy with NB-DNJ might be a promising approach for the treatment of GAA deficiency at least for the selected patients.
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Buenteweg 17, 30559 Hannover, Germany.|Fish Disease Research Unit, University of Veterinary Medicine Hannover, Buenteweg 17, D-30559 Hannover, Germany.
authors.forename: Graham
authors.initials: G
authors.lastname: Brogden
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Buenteweg 17, 30559 Hannover, Germany.|Department of Paediatrics, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.
authors.forename: Hadeel
authors.initials: H
authors.lastname: Shammas
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Buenteweg 17, 30559 Hannover, Germany.|Department of Paediatrics, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.
authors.forename: Katia
authors.initials: K
authors.lastname: Maalouf
authors.affiliation: Department of Paediatrics, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.|Faculty of Science, University of Fribourg, Switzerland.
authors.forename: Samara L
authors.initials: SL
authors.lastname: Naim
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Buenteweg 17, 30559 Hannover, Germany.
authors.forename: Gabi
authors.initials: G
authors.lastname: Wetzel
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Buenteweg 17, 30559 Hannover, Germany.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Amiri
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Buenteweg 17, 30559 Hannover, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: von Köckritz-Blickwede
authors.affiliation: Department of Paediatrics, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany hassan.naim@tiho-hannover.de Das.Anibh@mh-hannover.de.
authors.forename: Anibh M
authors.initials: AM
authors.lastname: Das
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Buenteweg 17, 30559 Hannover, Germany hassan.naim@tiho-hannover.de Das.Anibh@mh-hannover.de.
authors.forename: Hassan Y
authors.initials: HY
authors.lastname: Naim
mesh_terms: D000328:Adult; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D000795:Fabry Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006017:Glycolipids / Q000378:metabolism; D006801:Humans; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism*; D010084:Oxidation-Reduction; D017354:Point Mutation; D021381:Protein Transport; D013109:Sphingomyelins / Q000378:metabolism; D014281:Trihexosylceramides / Q000378:metabolism; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D006017:Glycolipids; D008563:Membrane Lipids; D013109:Sphingomyelins; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D000519:alpha-Galactosidase
keywords: lipid rafts; lipids; lysosomal storage disease; membranes