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Bi-allelic VPS16 va...
Bi-allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis-like disease.
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- Sofou, Kalliopi (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institute of Clinical Sciences, Department of Pediatrics
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Meier, Kolja (author)
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Sanderson, Leslie E (author)
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- Kaminski, Debora (author)
- Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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- Montoliu-Gaya, Laia (author)
- Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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Samuelsson, Emma (author)
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- Blomqvist, Maria K., 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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- Agholme, Lotta (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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Gärtner, Jutta (author)
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Mühlhausen, Chris (author)
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- Darin, Niklas, 1964 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institute of Clinical Sciences, Department of Pediatrics
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Barakat, Tahsin Stefan (author)
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Schlotawa, Lars (author)
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van Ham, Tjakko (author)
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- Asin-Cayuela, Jorge (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Department of Laboratory Medicine
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- Sterky, Fredrik H (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Wallenberg Centre for Molecular and Translational Medicine,Department of Laboratory Medicine
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(creator_code:org_t)
- 2021-05-03
- 2021
- English.
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In: EMBO molecular medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 13
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https://doi.org/10.1...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Klinisk laboratoriemedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Clinical Laboratory Medicine (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
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- ref (subject category)
- art (subject category)
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- By the author/editor
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Sofou, Kalliopi
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Meier, Kolja
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Sanderson, Lesli ...
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Kaminski, Debora
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Montoliu-Gaya, L ...
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Samuelsson, Emma
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show more...
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Blomqvist, Maria ...
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Agholme, Lotta
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Gärtner, Jutta
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Mühlhausen, Chri ...
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Darin, Niklas, 1 ...
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Barakat, Tahsin ...
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Schlotawa, Lars
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van Ham, Tjakko
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Asin-Cayuela, Jo ...
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Sterky, Fredrik ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Clinical Laborat ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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EMBO molecular m ...
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University of Gothenburg