Arylsulfatase K inactivation causes mucopolysaccharidosis due to deficient glucuronate desulfation of heparan and chondroitin sulfate

Christof Trabszo, Bastian Ramms, Pradeep Chopra, Renate Lüllmann-Rauch, Stijn Stroobants, Jens Sproß, Anke Jeschke, Thorsten Schinke, Geert-Jan Boons, Jeffrey Esko, Torben Lübke, Thomas Dierks

Research output: Contribution to journalArticleAcademicpeer-review


Mucopolysaccharidoses comprise a group of rare metabolic diseases, in which the lysosomal degradation of glycosaminoglycans (GAGs) is impaired due to genetically inherited defects of lysosomal enzymes involved in GAG catabolism. The resulting intralysosomal accumulation of GAG-derived metabolites consequently manifests in neurological symptoms and also peripheral abnormalities in various tissues like liver, kidney, spleen and bone. As each GAG consists of differently sulfated disaccharide units, it needs a specific, but also partly overlapping set of lysosomal enzymes to accomplish their complete degradation. Recently, we identified and characterized the lysosomal enzyme arylsulfatase K (Arsk) exhibiting glucuronate-2-sulfatase activity as needed for the degradation of heparan sulfate, chondroitin sulfate and dermatan sulfate. In the present study, we investigated the physiological relevance of Arsk by means of a constitutive Arsk knockout mouse model. A complete lack of glucuronate desulfation was demonstrated by a specific enzyme activity assay. Arsk-deficient mice show, in an organ-specific manner, a moderate accumulation of heparan sulfate and chondroitin sulfate metabolites characterized by 2-O-sulfated glucuronate moieties at their non-reducing ends. Pathophysiological studies reflect a rather mild phenotype including behavioral changes. Interestingly, no prominent lysosomal storage pathology like bone abnormalities were detected. Our results from the Arsk mouse model suggest a new although mild form of MPS, which we designate MPS type IIB.

Original languageEnglish
Pages (from-to)3433–3451
JournalBiochemical Journal
Issue number17
Early online date28 Aug 2020
Publication statusPublished - Sept 2020


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