The lysosomal disease caused by mutant VPS33A
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...
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ftpubmed:oai:pubmedcentral.nih.gov:6644154 2023-05-15T18:45:16+02:00 The lysosomal disease caused by mutant VPS33A Pavlova, Elena V Shatunov, Aleksey Wartosch, Lena Moskvina, Alena I Nikolaeva, Lena E Bright, Nicholas A Tylee, Karen L Church, Heather J Ballabio, Andrea Luzio, J Paul Cox, Timothy M 2019-08-01 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644154/ http://www.ncbi.nlm.nih.gov/pubmed/31070736 https://doi.org/10.1093/hmg/ddz077 en eng Oxford University Press http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644154/ http://www.ncbi.nlm.nih.gov/pubmed/31070736 http://dx.doi.org/10.1093/hmg/ddz077 © The Author(s) 2019. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. CC-BY General Article Text 2019 ftpubmed https://doi.org/10.1093/hmg/ddz077 2019-08-04T00:56:57Z 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. Text Yakuts Siberia PubMed Central (PMC) Human Molecular Genetics 28 15 2514 2530 |
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General Article Pavlova, Elena V Shatunov, Aleksey Wartosch, Lena Moskvina, Alena I Nikolaeva, Lena E Bright, Nicholas A Tylee, Karen L Church, Heather J Ballabio, Andrea Luzio, J Paul Cox, Timothy M The lysosomal disease caused by mutant VPS33A |
topic_facet |
General Article |
description |
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. |
format |
Text |
author |
Pavlova, Elena V Shatunov, Aleksey Wartosch, Lena Moskvina, Alena I Nikolaeva, Lena E Bright, Nicholas A Tylee, Karen L Church, Heather J Ballabio, Andrea Luzio, J Paul Cox, Timothy M |
author_facet |
Pavlova, Elena V Shatunov, Aleksey Wartosch, Lena Moskvina, Alena I Nikolaeva, Lena E Bright, Nicholas A Tylee, Karen L Church, Heather J Ballabio, Andrea Luzio, J Paul Cox, Timothy M |
author_sort |
Pavlova, Elena V |
title |
The lysosomal disease caused by mutant VPS33A |
title_short |
The lysosomal disease caused by mutant VPS33A |
title_full |
The lysosomal disease caused by mutant VPS33A |
title_fullStr |
The lysosomal disease caused by mutant VPS33A |
title_full_unstemmed |
The lysosomal disease caused by mutant VPS33A |
title_sort |
lysosomal disease caused by mutant vps33a |
publisher |
Oxford University Press |
publishDate |
2019 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644154/ http://www.ncbi.nlm.nih.gov/pubmed/31070736 https://doi.org/10.1093/hmg/ddz077 |
genre |
Yakuts Siberia |
genre_facet |
Yakuts Siberia |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644154/ http://www.ncbi.nlm.nih.gov/pubmed/31070736 http://dx.doi.org/10.1093/hmg/ddz077 |
op_rights |
© The Author(s) 2019. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
op_rightsnorm |
CC-BY |
op_doi |
https://doi.org/10.1093/hmg/ddz077 |
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Human Molecular Genetics |
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28 |
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15 |
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2514 |
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2530 |
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1766236311399694336 |