PUBLICATION
Loss of zebrafish atp6v1e1b, encoding a subunit of vacuolar ATPase, recapitulates human ARCL type 2C syndrome and identifies multiple pathobiological signatures
- Authors
- Pottie, L., Van Gool, W., Vanhooydonck, M., Hanisch, F.G., Goeminne, G., Rajkovic, A., Coucke, P., Sips, P., Callewaert, B.
- ID
- ZDB-PUB-210622-26
- Date
- 2021
- Source
- PLoS Genetics 17: e1009603 (Journal)
- Registered Authors
- Callewaert, Bert, Coucke, Paul, Sips, Patrick
- Keywords
- none
- MeSH Terms
-
- Disease Models, Animal
- Epithelial Cells/metabolism*
- Epithelial Cells/pathology
- Protein Isoforms/deficiency
- Protein Isoforms/genetics
- Lipidomics
- Lysosomes/metabolism
- Lysosomes/pathology
- Humans
- Endosomes/metabolism
- Endosomes/pathology
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics*
- Larva/genetics
- Larva/growth & development
- Larva/metabolism
- Metabolome/genetics
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- Longevity/genetics
- Cutis Laxa/genetics*
- Cutis Laxa/metabolism
- Cutis Laxa/pathology
- Transcriptome
- Skin/metabolism*
- Skin/pathology
- Syndrome
- Abnormalities, Multiple/genetics*
- Abnormalities, Multiple/metabolism
- Abnormalities, Multiple/pathology
- Mitochondria/metabolism
- Mitochondria/pathology
- Oxidative Phosphorylation
- Vacuolar Proton-Translocating ATPases/deficiency
- Vacuolar Proton-Translocating ATPases/genetics*
- Animals
- Gene Expression Regulation
- PubMed
- 34143769 Full text @ PLoS Genet.
Citation
Pottie, L., Van Gool, W., Vanhooydonck, M., Hanisch, F.G., Goeminne, G., Rajkovic, A., Coucke, P., Sips, P., Callewaert, B. (2021) Loss of zebrafish atp6v1e1b, encoding a subunit of vacuolar ATPase, recapitulates human ARCL type 2C syndrome and identifies multiple pathobiological signatures. PLoS Genetics. 17:e1009603.
Abstract
The inability to maintain a strictly regulated endo(lyso)somal acidic pH through the proton-pumping action of the vacuolar-ATPases (v-ATPases) has been associated with various human diseases including heritable connective tissue disorders. Autosomal recessive (AR) cutis laxa (CL) type 2C syndrome is associated with genetic defects in the ATP6V1E1 gene and is characterized by skin wrinkles or loose redundant skin folds with pleiotropic systemic manifestations. The underlying pathological mechanisms leading to the clinical presentations remain largely unknown. Here, we show that loss of atp6v1e1b in zebrafish leads to early mortality, associated with craniofacial dysmorphisms, vascular anomalies, cardiac dysfunction, N-glycosylation defects, hypotonia, and epidermal structural defects. These features are reminiscent of the phenotypic manifestations in ARCL type 2C patients. Our data demonstrates that loss of atp6v1e1b alters endo(lyso)somal protein levels, and interferes with non-canonical v-ATPase pathways in vivo. In order to gain further insights into the processes affected by loss of atp6v1e1b, we performed an untargeted analysis of the transcriptome, metabolome, and lipidome in early atp6v1e1b-deficient larvae. We report multiple affected pathways including but not limited to oxidative phosphorylation, sphingolipid, fatty acid, and energy metabolism together with profound defects on mitochondrial respiration. Taken together, our results identify complex pathobiological effects due to loss of atp6v1e1b in vivo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping