Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A

Elena V. Pavlova*, Dorit Lev, Marina Michelson, Keren Yosovich, Hila Gur Michaeli, Nicholas A. Bright, Paul T. Manna, Veronica Kane Dickson, Karen L. Tylee, Heather J. Church, J. Paul Luzio, Timothy M. Cox

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components of the intracellular membrane-tethering protein complexes, HOPS, and CORVET. Whole exome sequencing identified a novel VPS33A mutation in a patient suffering from a variant form of mucopolysaccharidosis. Electron and confocal microscopy, immunoblotting, and glycosphingolipid trafficking experiments were undertaken to investigate the effects of the mutant VPS33A in patient-derived skin fibroblasts. We describe an attenuated juvenile form of VPS33A-related syndrome—mucopolysaccharidosis plus in a man who is homozygous for a hitherto unknown missense mutation (NM_022916.4: c.599 G>C; NP_075067.2:p. Arg200Pro) in a conserved region of the VPS33A gene. Urinary glycosaminoglycan (GAG) analysis revealed increased heparan, dermatan sulphates, and hyaluronic acid. We showed decreased abundance of VPS33A in patient derived fibroblasts and provided evidence that the p.Arg200Pro mutation leads to destablization of the protein and proteasomal degradation. As in the infantile form of mucopolysaccharidosis plus, the endocytic compartment in the fibroblasts also expanded—a phenomenon accompanied by increased endolysosomal acidification and impaired intracellular glycosphingolipid trafficking. Experimental treatment of the patient's cultured fibroblasts with the proteasome inhibitor, bortezomib, or exposure to an inhibitor of glucosylceramide synthesis, eliglustat, improved glycosphingolipid trafficking. To our knowledge this is the first report of an attenuated juvenile form of VPS33A insufficiency characterized by appreciable residual endosomal-lysosomal trafficking and a milder mucopolysaccharidosis plus than the disease in infants. Our findings expand the proof of concept of redeploying clinically approved drugs for therapeutic exploitation in patients with juvenile as well as infantile forms of mucopolysaccharidosis plus disease.

Original languageEnglish
Pages (from-to)2265-2278
Number of pages14
JournalHuman Mutation
Issue number12
StatePublished - Dec 2022


FundersFunder number
H2020 Marie Skłodowska-Curie Actions
University Hospitals Bristol NHS Foundation Trust
Global Challenges Research FundQR AY2019‐20
Medical Research CouncilMR/R009015/1
National Institute for Health and Care ResearchBRC‐1215‐20014
Horizon 2020101030247


    • VPS33A
    • drug repurposing
    • endolysosomal acidification
    • glycosaminoglycan
    • glycosphingolipid trafficking
    • intracellular endocytic trafficking
    • mucopolysaccharidosis
    • proteasome inhibitor
    • substrate reduction therapy


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