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VPS33A is a core component of the class C core vacuole\/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes, which have essential functions in the endocytic pathway. Here we show that cultured fibroblasts from patients with this disorder have morphological changes: vacuolation with disordered endosomal\/lysosomal compartments and\u2014common to sphingolipid diseases\u2014abnormal endocytic trafficking of lactosylceramide. Urine glycosaminoglycan studies revealed a pathological excess of sialylated conjugates as well as dermatan and heparan sulphate. Lipidomic screening showed elevated \u03b2-D-galactosylsphingosine with unimpaired activity of cognate lysosomal hydrolases. The 3D crystal structure of human VPS33A predicts that replacement of arginine 498 by tryptophan will de-stabilize VPS33A folding. We observed that the missense mutation reduced the abundance of full-length VPS33A and other components of the HOPS and CORVET complexes. Treatment of HeLa cells stably expressing the mutant VPS33A with a proteasome inhibitor rescued the mutant protein from degradation. We propose that the disease is due to diminished intracellular abundance of intact VPS33A. Exposure of patient-derived fibroblasts to the clinically approved proteasome inhibitor, bortezomib, or inhibition of glucosylceramide synthesis with eliglustat, partially corrected the impaired lactosylceramide trafficking defect and immediately suggest therapeutic avenues to explore in this fatal orphan disease.<\/jats:p>","DOI":"10.1093\/hmg\/ddz077","type":"journal-article","created":{"date-parts":[[2019,4,9]],"date-time":"2019-04-09T15:56:58Z","timestamp":1554825418000},"page":"2514-2530","source":"Crossref","is-referenced-by-count":43,"title":["The lysosomal disease caused by mutant VPS33A"],"prefix":"10.1093","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0187-5098","authenticated-orcid":false,"given":"Elena V","family":"Pavlova","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksey","family":"Shatunov","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King\u2019s College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Wartosch","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research and Department of Clinical Biochemistry, Wellcome Trust\/MRC Building, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena I","family":"Moskvina","sequence":"additional","affiliation":[{"name":"Paediatric Centre, National Medical Centre of the Republic of Sakha, Yakutsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena E","family":"Nikolaeva","sequence":"additional","affiliation":[{"name":"Paediatric Centre, National Medical Centre of the Republic of Sakha, Yakutsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas A","family":"Bright","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research and Department of Clinical Biochemistry, Wellcome Trust\/MRC Building, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L","family":"Tylee","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather J","family":"Church","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ballabio","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Paul","family":"Luzio","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research and Department of Clinical Biochemistry, Wellcome Trust\/MRC Building, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,4,10]]},"reference":[{"key":"2019072208595476600_ref1","first-page":"173","article-title":"Mutation in VPS33A affects metabolism of glycosaminoglycans: a new type of mucopolysaccharidosis with severe systemic symptoms","volume":"1","author":"Kondo","year":"2017","journal-title":"Hum. 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