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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ftunivnapoliiris:oai:www.iris.unina.it:11588/757508 2024-06-23T07:57:26+00:00 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 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 http://hdl.handle.net/11588/757508 https://doi.org/10.1093/hmg/ddz077 eng eng info:eu-repo/semantics/altIdentifier/wos/WOS:000493061600005 volume:28 issue:15 firstpage:2514 lastpage:2530 numberofpages:17 journal:HUMAN MOLECULAR GENETICS http://hdl.handle.net/11588/757508 doi:10.1093/hmg/ddz077 info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85075474089 info:eu-repo/semantics/article 2019 ftunivnapoliiris https://doi.org/10.1093/hmg/ddz077 2024-06-10T14:58:51Z 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. Article in Journal/Newspaper Yakuts Siberia IRIS Università degli Studi di Napoli Federico II Human Molecular Genetics 28 15 2514 2530 |
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IRIS Università degli Studi di Napoli Federico II |
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English |
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. |
author2 |
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 |
format |
Article in Journal/Newspaper |
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 |
spellingShingle |
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 |
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 |
publishDate |
2019 |
url |
http://hdl.handle.net/11588/757508 https://doi.org/10.1093/hmg/ddz077 |
genre |
Yakuts Siberia |
genre_facet |
Yakuts Siberia |
op_relation |
info:eu-repo/semantics/altIdentifier/wos/WOS:000493061600005 volume:28 issue:15 firstpage:2514 lastpage:2530 numberofpages:17 journal:HUMAN MOLECULAR GENETICS http://hdl.handle.net/11588/757508 doi:10.1093/hmg/ddz077 info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85075474089 |
op_doi |
https://doi.org/10.1093/hmg/ddz077 |
container_title |
Human Molecular Genetics |
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28 |
container_issue |
15 |
container_start_page |
2514 |
op_container_end_page |
2530 |
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1802651066063388672 |