2. Academic Validation
  3. Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency

Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency

  • J Med Genet. 2022 Oct;59(10):957-964. doi: 10.1136/jmedgenet-2021-108061.
Sarah Verheyen 1,  Jasmin Blatterer 1,  Michael R Speicher 1,  Gandham SriLakshmi Bhavani 2,  Geert-Jan Boons 3 4,  Mai-Britt Ilse 5,  Dominik Andrae 5,  Jens Sproß 6,  Frédéric Maxime Vaz 7,  Susanne G Kircher 8,  Laura Posch-Pertl 9,  Daniela Baumgartner 10,  Torben Lübke 5,  Hitesh Shah 11,  Ali Al Kaissi 12,  Katta M Girisha 13,  Barbara Plecko 14
Affiliations

Affiliations

  • 1 Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Graz, Austria.
  • 2 Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
  • 3 Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia, USA.
  • 4 Department of Chemistry, University of Georgia, Athens, Georgia, USA.
  • 5 Department of Chemistry, Biochemistry, Bielefeld University, Bielefeld, Germany.
  • 6 Faculty of Chemistry, Industrial Organic Chemistry and Biotechnology - Mass Spectrometry, Bielefeld University, Bielefeld, Germany.
  • 7 Laboratory Genetic Metabolic Disease, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Core Facility Metabolomics, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands, Amsterdam UMC Locatie Meibergdreef, Amsterdam, North Holland, The Netherlands.
  • 8 Institute of Medical Chemistry, Medical University of Vienna, Vienna, Austria.
  • 9 Department of Ophthalmology, Medical University of Graz, Graz, Austria.
  • 10 Department of Pediatrics and Adolescent Medicine; Division of Pediatric Cardiology, Medical University of Graz, Graz, Austria.
  • 11 Department of Orthopedics, Kasturba Medical College Manipal, Manipal, India.
  • 12 Pediatric Department, Speising Orthopaedic Hospital, Vienna, Austria.
  • 13 Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India [email protected] [email protected].
  • 14 Department of Pediatrics, Division of General Pediatrics, Medical University of Graz, Graz, Austria [email protected] [email protected].
PMID: 34916232 DOI: 10.1136/jmedgenet-2021-108061
Abstract

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.

Keywords

genetics; human genetics; orthopedics; pediatrics; phenotype.

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