Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A

Abstract

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

Drug Repurposing and Lysosomal Storage Disorders: A Trick to Treat

“…Sometimes, repositioning happens almost in real time with the case reporting of novel or exceedingly rare diseases. While reporting a case displaying mucopolysaccharidosis plus, a rare and attenuated subtype of mucopolysaccharidosis related to the VPS33A protein, Pavlova and co-workers described the effects of bortezomib and eliglustat in improving glycosphingolipid trafficking in patient-derived fibroblasts [ 71 ]. On the one hand, eliglustat is the drug approved for GD, and it acts as an inhibitor of glucosylceramide synthase, being used in substrate reduction therapies [ 72 ].…”

Prenatal Diagnosis of Mucopolysaccharidosis-Plus Syndrome (MPSPS)

“…Pavlova et al, have described the one possible variant, c.599G>C (p.R200P), in the VPS33A gene that might lead to MPSPS [ 8 ]. However, the patient revealed a mild phenotype and slow progress of the disease, which does not resemble MPSPS patients with variant c.1492C>T (p.R498W).…”