Bi‐allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis‐like disease
Abstract Lysosomal storage diseases, including mucopolysaccharidoses, result from genetic defects that impair lysosomal catabolism. Here, we describe two patients from two independent families presenting with progressive psychomotor regression, delayed myelination, brain atrophy, neutropenia, skelet...
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doaj-4136db5871f54bce829ae48563537d482021-08-02T21:23:19ZengWileyEMBO Molecular Medicine1757-46761757-46842021-05-01135n/an/a10.15252/emmm.202013376Bi‐allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis‐like diseaseKalliopi Sofou0Kolja Meier1Leslie E Sanderson2Debora Kaminski3Laia Montoliu‐Gaya4Emma Samuelsson5Maria Blomqvist6Lotta Agholme7Jutta Gärtner8Chris Mühlhausen9Niklas Darin10Tahsin Stefan Barakat11Lars Schlotawa12Tjakko vanHam13Jorge Asin Cayuela14Fredrik H Sterky15Department of Paediatrics Institute of Clinical Sciences University of Gothenburg Gothenburg SwedenDepartment of Pediatrics and Adolescent Medicine University Medical Center Goettingen Goettingen GermanyDepartment of Clinical Genetics Erasmus University Medical Center Rotterdam Rotterdam The NetherlandsDepartment of Laboratory Medicine Institute of Biomedicine University of Gothenburg Gothenburg SwedenDepartment of Laboratory Medicine Institute of Biomedicine University of Gothenburg Gothenburg SwedenDepartment of Clinical Chemistry Sahlgrenska University Hospital Gothenburg SwedenDepartment of Laboratory Medicine Institute of Biomedicine University of Gothenburg Gothenburg SwedenDepartment of Clinical Chemistry Sahlgrenska University Hospital Gothenburg SwedenDepartment of Pediatrics and Adolescent Medicine University Medical Center Goettingen Goettingen GermanyDepartment of Pediatrics and Adolescent Medicine University Medical Center Goettingen Goettingen GermanyDepartment of Paediatrics Institute of Clinical Sciences University of Gothenburg Gothenburg SwedenDepartment of Clinical Genetics Erasmus University Medical Center Rotterdam Rotterdam The NetherlandsDepartment of Pediatrics and Adolescent Medicine University Medical Center Goettingen Goettingen GermanyDepartment of Clinical Genetics Erasmus University Medical Center Rotterdam Rotterdam The NetherlandsDepartment of Laboratory Medicine Institute of Biomedicine University of Gothenburg Gothenburg SwedenDepartment of Laboratory Medicine Institute of Biomedicine University of Gothenburg Gothenburg SwedenAbstract Lysosomal storage diseases, including mucopolysaccharidoses, result from genetic defects that impair lysosomal catabolism. Here, we describe two patients from two independent families presenting with progressive psychomotor regression, delayed myelination, brain atrophy, neutropenia, skeletal abnormalities, and mucopolysaccharidosis‐like dysmorphic features. Both patients were homozygous for the same intronic variant in VPS16, a gene encoding a subunit of the HOPS and CORVET complexes. The variant impaired normal mRNA splicing and led to an ~85% reduction in VPS16 protein levels in patient‐derived fibroblasts. Levels of other HOPS/CORVET subunits, including VPS33A, were similarly reduced, but restored upon re‐expression of VPS16. Patient‐derived fibroblasts showed defects in the uptake and endosomal trafficking of transferrin as well as accumulation of autophagosomes and lysosomal compartments. Re‐expression of VPS16 rescued the cellular phenotypes. Zebrafish with disrupted vps16 expression showed impaired development, reduced myelination, and a similar accumulation of lysosomes and autophagosomes in the brain, particularly in glia cells. This disorder resembles previously reported patients with mutations in VPS33A, thus expanding the family of mucopolysaccharidosis‐like diseases that result from mutations in HOPS/CORVET subunits.https://doi.org/10.15252/emmm.202013376autophagyendosomelysosomal storage diseaseMPSmyelination |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kalliopi Sofou Kolja Meier Leslie E Sanderson Debora Kaminski Laia Montoliu‐Gaya Emma Samuelsson Maria Blomqvist Lotta Agholme Jutta Gärtner Chris Mühlhausen Niklas Darin Tahsin Stefan Barakat Lars Schlotawa Tjakko vanHam Jorge Asin Cayuela Fredrik H Sterky |
spellingShingle |
Kalliopi Sofou Kolja Meier Leslie E Sanderson Debora Kaminski Laia Montoliu‐Gaya Emma Samuelsson Maria Blomqvist Lotta Agholme Jutta Gärtner Chris Mühlhausen Niklas Darin Tahsin Stefan Barakat Lars Schlotawa Tjakko vanHam Jorge Asin Cayuela Fredrik H Sterky Bi‐allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis‐like disease EMBO Molecular Medicine autophagy endosome lysosomal storage disease MPS myelination |
author_facet |
Kalliopi Sofou Kolja Meier Leslie E Sanderson Debora Kaminski Laia Montoliu‐Gaya Emma Samuelsson Maria Blomqvist Lotta Agholme Jutta Gärtner Chris Mühlhausen Niklas Darin Tahsin Stefan Barakat Lars Schlotawa Tjakko vanHam Jorge Asin Cayuela Fredrik H Sterky |
author_sort |
Kalliopi Sofou |
title |
Bi‐allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis‐like disease |
title_short |
Bi‐allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis‐like disease |
title_full |
Bi‐allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis‐like disease |
title_fullStr |
Bi‐allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis‐like disease |
title_full_unstemmed |
Bi‐allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis‐like disease |
title_sort |
bi‐allelic vps16 variants limit hops/corvet levels and cause a mucopolysaccharidosis‐like disease |
publisher |
Wiley |
series |
EMBO Molecular Medicine |
issn |
1757-4676 1757-4684 |
publishDate |
2021-05-01 |
description |
Abstract Lysosomal storage diseases, including mucopolysaccharidoses, result from genetic defects that impair lysosomal catabolism. Here, we describe two patients from two independent families presenting with progressive psychomotor regression, delayed myelination, brain atrophy, neutropenia, skeletal abnormalities, and mucopolysaccharidosis‐like dysmorphic features. Both patients were homozygous for the same intronic variant in VPS16, a gene encoding a subunit of the HOPS and CORVET complexes. The variant impaired normal mRNA splicing and led to an ~85% reduction in VPS16 protein levels in patient‐derived fibroblasts. Levels of other HOPS/CORVET subunits, including VPS33A, were similarly reduced, but restored upon re‐expression of VPS16. Patient‐derived fibroblasts showed defects in the uptake and endosomal trafficking of transferrin as well as accumulation of autophagosomes and lysosomal compartments. Re‐expression of VPS16 rescued the cellular phenotypes. Zebrafish with disrupted vps16 expression showed impaired development, reduced myelination, and a similar accumulation of lysosomes and autophagosomes in the brain, particularly in glia cells. This disorder resembles previously reported patients with mutations in VPS33A, thus expanding the family of mucopolysaccharidosis‐like diseases that result from mutations in HOPS/CORVET subunits. |
topic |
autophagy endosome lysosomal storage disease MPS myelination |
url |
https://doi.org/10.15252/emmm.202013376 |
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