Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A.

Autor: Pavlova EV; Department of Medicine, University of Cambridge, Cambridge, UK., Lev D; Wolfson Medical Centre, Institute of Medical Genetics, Holon, Israel.; The Rina Mor Institute of Medical Genetics, Holon, Israel.; The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Michelson M; Wolfson Medical Centre, Institute of Medical Genetics, Holon, Israel., Yosovich K; Wolfson Medical Centre, Institute of Medical Genetics, Holon, Israel., Michaeli HG; Wolfson Medical Centre, Institute of Medical Genetics, Holon, Israel., Bright NA; Department of Clinical Biochemistry, Cambridge Institute for Medical Research, The Keith Peters Building, University of Cambridge, Cambridge, UK., Manna PT; Department of Clinical Biochemistry, Cambridge Institute for Medical Research, The Keith Peters Building, University of Cambridge, Cambridge, UK.; Department of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden., Dickson VK; Department of Clinical Biochemistry, Cambridge Institute for Medical Research, The Keith Peters Building, University of Cambridge, Cambridge, UK., Tylee KL; Willink Biochemical Genetics Unit, Genomic Diagnostics Laboratory, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust St Mary's Hospital, Manchester, UK., Church HJ; Willink Biochemical Genetics Unit, Genomic Diagnostics Laboratory, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust St Mary's Hospital, Manchester, UK., Luzio JP; Department of Clinical Biochemistry, Cambridge Institute for Medical Research, The Keith Peters Building, University of Cambridge, Cambridge, UK., Cox TM; Department of Medicine, University of Cambridge, Cambridge, UK.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2022 Dec; Vol. 43 (12), pp. 2265-2278. Date of Electronic Publication: 2022 Oct 08.
DOI: 10.1002/humu.24479
Abstrakt: 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.
(© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)
Databáze: MEDLINE
Externí odkaz: