Multiple sulfatase deficiency (MSD),
mucolipidosis (
ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-
lysosomal proteins. The
NPC1 protein mainly localizes to late endosomes and is essential for
cholesterol redistribution from endocytosed
LDL to cellular membranes. NPC1 deficiency leads to lysosomal accumulation of a broad range of
lipids. The precise functional mechanism of this
membrane protein, however, remains puzzling.
ML II, also termed
I cell disease, and the less severe ML III result from deficiencies of the Golgi
enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized
lysosomal proteins are not equipped with the critical lysosomal trafficking marker
mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire
sulfatase family, at least seven members of which are lysosomal
enzymes that are specifically involved in the degradation of sulfated
glycosaminoglycans,
sulfolipids or other sulfated molecules. The combined deficiencies of all
sulfatases result from a defective post-translational modification by the ER-localized
formylglycine-generating
enzyme (FGE), which oxidizes a specific
cysteine residue to
formylglycine, the catalytic residue enabling a unique mechanism of
sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been addressed. Further, the discovery of FGE as an essential
sulfatase activating
enzyme has considerable impact on
enzyme replacement or gene therapy of lysosomal storage disorders caused by single
sulfatase deficiencies.