Bi‐allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis‐like disease

EMBO Molecular Medicine

卷:13

Emma Samuelsson¹  Lotta Agholme¹  Leslie E Sanderson²  Tahsin Stefan Barakat²  Tjakko vanHam²  Laia Montoliu‐Gaya³  Maria Blomqvist³  Fredrik H Sterky³  Jorge Asin Cayuela³  Debora Kaminski³  Niklas Darin⁴  Kalliopi Sofou⁴  Jutta Gärtner⁵  Lars Schlotawa⁵  Kolja Meier⁵  Chris Mühlhausen⁵ 

[1] Department of Clinical Chemistry Sahlgrenska University Hospital Gothenburg Sweden;

[2] Department of Clinical Genetics Erasmus University Medical Center Rotterdam Rotterdam The Netherlands;

[3] Department of Laboratory Medicine Institute of Biomedicine University of Gothenburg Gothenburg Sweden;

[4] Department of Paediatrics Institute of Clinical Sciences University of Gothenburg Gothenburg Sweden;

[5] Department of Pediatrics and Adolescent Medicine University Medical Center Goettingen Goettingen Germany;

关键词: autophagy;    endosome;    lysosomal storage disease;    MPS;    myelination;   

DOI  :  10.15252/emmm.202013376

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown