TY - JOUR T1 - Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2021-108061 SP - jmedgenet-2021-108061 AU - Sarah Verheyen AU - Jasmin Blatterer AU - Michael R Speicher AU - Gandham SriLakshmi Bhavani AU - Geert-Jan Boons AU - Mai-Britt Ilse AU - Dominik Andrae AU - Jens Sproß AU - Frédéric Maxime Vaz AU - Susanne G Kircher AU - Laura Posch-Pertl AU - Daniela Baumgartner AU - Torben Lübke AU - Hitesh Shah AU - Ali Al Kaissi AU - Katta M Girisha AU - Barbara Plecko Y1 - 2021/12/16 UR - http://jmg.bmj.com/content/early/2021/12/15/jmedgenet-2021-108061.abstract N2 - Background Mucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I–IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate. Knockout of Arsk in mice was consistent with mild storage pathology, but no human phenotype has yet been described.Methods In this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Functional consequences of the two ARSK variants were assessed by mutation-specific ARSK constructs derived by site-directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LC-MS)/MS analysis.Results The phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS.Conclusion Our work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X.Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Data supporting this paper are provided within the article and Supplementary file. Any additional data not compromised by ethical issues will be made available upon request. ER -