ArticleHuman molecular genetics2019
The lysosomal disease caused by mutant VPS33A.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 40 citations in OpenAlex.
- Severe neurodevelopmental phenotype with multisystem involvement in VPS16-related mucopolysaccharidosis-like syndrome.Neurogenetics · 2026Article
- Cellular and molecular changes in mucopolysaccharidosis-plus syndrome caused by a homozygous c.599G > C (p.Arg200Pro) variant of the VPS33A gene.Journal of applied genetics · 2026Article
- VPS33A Promotes Pemigatinib Resistance in Cholangiocarcinoma via Autophagy.Digestive diseases and sciences · 2026Article
- Mutations in VPS18 lead to a neutrophil maturation defect associated with disturbed vesicle homeostasis.Cell death & disease · 2026Article
- The use of genistein and ambroxol may be an effective approach in correcting cellular dysfunctions of mucopolysaccharidosis-plus syndrome.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Cell Trafficking Disorders Play an Important Role in the Pathogenesis of Skeletal Dysplasias.Turkish archives of pediatrics · 2025Article
- Article
- The Birth Prevalence of Mucopolysaccharidosis Types I, II, III, IVA, VI, and VII in the Republic of Kazakhstan Between 1984 and 2023.Diagnostics (Basel, Switzerland) · 2025Article
- Unifying biology of neurodegeneration in lysosomal storage diseases.Journal of inherited metabolic disease · 2025Review
- Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening.Cell systems · 2024Article
- Mannose receptor (MRC1) mediates uptake of dextran by bone marrow-derived macrophages.Molecular biology of the cell · 2024Article
- Mucopolysaccharidosis-Plus Syndrome: Is This a Type of Mucopolysaccharidosis or a Separate Kind of Metabolic Disease?International journal of molecular sciences · 2024Review
- HypomyelinatedInternational journal of molecular sciences · 2024Article
- Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening.bioRxiv : the preprint server for biology · 2024Article
- Clinical and biochemical footprints of inherited metabolic diseases. XIV. Metabolic kidney diseases.Molecular genetics and metabolism · 2023Article
- HOPS, CORVET and newly-identified Hybrid tethering complexes contribute differentially towards multiple modes of endocytosis.Scientific reports · 2023Article
- Omics-Based Approaches for the Characterization of Pompe Disease Metabolic Phenotypes.Biology · 2023Review
- Article
- Lipidomics-Paving the Road towards Better Insight and Precision Medicine in Rare Metabolic Diseases.International journal of molecular sciences · 2023Review
- Juvenile mucopolysaccharidosis plus disease caused by a missense mutation in VPS33A.Human mutation · 2022Article
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
Abstract
A rare lysosomal disease resembling a mucopolysaccharidosis with unusual systemic features, including renal disease and platelet dysfunction, caused by the defect in a conserved region of the VPS33A gene on human chromosome 12q24.31, occurs in Yakuts-a nomadic Turkic ethnic group of Southern Siberia. 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-common to sphingolipid diseases-abnormal 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 β-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.
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