Case study on the pathophysiology of Fabry disease: abnormalities of cellular membranes can be reversed by substrate reduction in vitro

• Published in: Bioscience reports Vol. 37; no. 2
• Main Authors: Brogden, Graham, Shammas, Hadeel, Maalouf, Katia, Naim, Samara L, Wetzel, Gabi, Amiri, Mahdi, von Köckritz-Blickwede, Maren, Das, Anibh M, Naim, Hassan Y
• Format: Journal Article
• Language: English
• Published: England Portland Press Ltd 30.04.2017
• Subjects: Adult; alpha-Galactosidase - genetics; alpha-Galactosidase - metabolism; Cell Membrane - metabolism; Cell Membrane - pathology; Cells, Cultured; Fabry Disease - genetics; Fabry Disease - metabolism; Fabry Disease - physiopathology; Fibroblasts - metabolism; Fibroblasts - pathology; Glycolipids - metabolism; Humans; Male; Membrane Lipids - metabolism; Oxidation-Reduction; Point Mutation; Protein Transport; Sphingomyelins - metabolism; Trihexosylceramides - metabolism; membranes; lipid rafts; lipids; lysosomal storage disease
• ISSN: 0144-8463; 1573-4935
• DOI: 10.1042/BSR20160402

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 with -butyldeoxynojirimycin (NB-DNJ) was 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.