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

Abnormalities, Multiple/genetics*
Abnormalities, Multiple/metabolism
Abnormalities, Multiple/pathology
Longevity/genetics
Zebrafish Proteins/deficiency
Zebrafish Proteins/genetics*
Zebrafish/embryology
Zebrafish/genetics
Zebrafish/metabolism
Oxidative Phosphorylation
Skin/metabolism*
Skin/pathology
Mitochondria/metabolism
Mitochondria/pathology
Protein Isoforms/deficiency
Protein Isoforms/genetics
Syndrome
Cutis Laxa/genetics*
Cutis Laxa/metabolism
Cutis Laxa/pathology
Metabolome/genetics
Animals
Disease Models, Animal
Gene Expression Regulation
Humans
Lipidomics
Endosomes/metabolism
Endosomes/pathology
Vacuolar Proton-Translocating ATPases/deficiency
Vacuolar Proton-Translocating ATPases/genetics*
Transcriptome
Larva/genetics
Larva/growth & development
Larva/metabolism
Epithelial Cells/metabolism*
Epithelial Cells/pathology
Lysosomes/metabolism
Lysosomes/pathology

(all 38)

PubMed

34143769 Full text @ PLoS Genet.

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

Figures