Journal Article

Saposin C mutations in Gaucher disease patients resulting in lysosomal lipid accumulation, saposin C deficiency, but normal prosaposin processing and sorting

Anna M. Vaccaro, Marialetizia Motta, Massimo Tatti, Susanna Scarpa, Laura Masuelli, Meenakshi Bhat, Marie T. Vanier, Anna Tylki-Szymanska and Rosa Salvioli

in Human Molecular Genetics

Volume 19, issue 15, pages 2987-2997
Published in print August 2010 | ISSN: 0964-6906
Published online May 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq204
Saposin C mutations in Gaucher disease patients resulting in lysosomal lipid accumulation, saposin C deficiency, but normal prosaposin processing and sorting

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Gaucher disease (GD) is characterized by accumulation of glucosylceramide (GC) in the cells of monocyte/macrophage system. The degradation of GC is controlled by glucosylceramidase (GCase) and saposin (Sap) C, a member of a family of four small glycoproteins (Saps A, B, C and D), all derived by proteolytic processing of a common precursor, prosaposin (PSAP). Saps contain six cysteine residues, forming three disulfide bridges, that affect their structure and function. Sap C is an essential activator of GCase and its deficit impairs the GCase activity causing GD. In the present study the biological properties of cells from four recently described GD patients carrying mutations in the Sap C domain of the PSAP gene have been characterized. Two patients had mutations involving a cysteine residue, whereas the other two had a L349P mutation. It was found that: (i) in the four Sap C-deficient cells PSAP was normally processed and sorted, the lack of Sap C being mainly due to the Sap C instability in late endosomal/lysosomal environment; (ii) the decrease/absence of Sap C affected the GCase intracellular localization; (iii) the lowest level of Sap C and enhanced autophagy were observed in the cells, which carried a Sap C mutation involving a cysteine residue; (iv) the four Sap C-deficient fibroblasts stored GC, ceramide and cholesterol, the last two lipids being clearly localized in lysosomes; (v) a correlation was observed between the type of Sap C mutation and the Gaucher phenotype: apparently, mutations involving cysteine residues lead to a neurological variant of GD.

Journal Article.  6811 words.  Illustrated.

Subjects: Genetics and Genomics

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