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 with N-butyldeoxynojirimycin (NB-DNJ) in vitro 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.
Highlights
Fabry disease (FD, MIM ID # 301500) known as Anderson disease in the Anglo-American literature is a multisystemic disease caused by deficiency of the lysosomal enzyme α-galactosidase A (GAA) [1]
We have shown that trafficking of a representative protein associated with detergent-resistant membranes (DRM)/lipid rafts (LRs), namely dipeptidyl peptidase IV (DPPIV), to the cell surface was hampered in fibroblasts from a Fabry patient, which may lead to altered signalling and transport at the cell surface [7]
Our results support the view that disturbances of the glyco- and sphingolipid balance in cell membranes in Fabry fibroblasts are associated with alterations in LRs, which are enriched in these types of membrane lipids
Summary
Fabry disease (FD, MIM ID # 301500) known as Anderson disease in the Anglo-American literature is a multisystemic disease caused by deficiency of the lysosomal enzyme α-galactosidase A (GAA) [1]. It is inherited as an X-linked trait, the phenotype is generally more severe in male hemizygotes as compared with female heterozygotes [2]. As a result of GAA deficiency, biodegradation of glycosphingolipids is compromised, which leads to the intralysosomal accumulation of terminal galactosyl containing neutral lipids [4]. The concept that clinical symptoms are directly related to storage of glycolipids resulting in ischaemia of organs is at best simplistic indicating that other functional disturbances must occur
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