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Loss of zebrafish atp6v1e1b, encoding a subunit of vacuolar ATPase, recapitulates human ARCL type 2C syndrome and identifies multiple pathobiological signatures.

Authors :
Lore Pottie
Wouter Van Gool
Michiel Vanhooydonck
Franz-Georg Hanisch
Geert Goeminne
Andreja Rajkovic
Paul Coucke
Patrick Sips
Bert Callewaert
Source :
PLoS Genetics, Vol 17, Iss 6, p e1009603 (2021)
Publication Year :
2021
Publisher :
Public Library of Science (PLoS), 2021.

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.

Subjects

Subjects :
Genetics
QH426-470

Details

Language :
English
ISSN :
15537390 and 15537404
Volume :
17
Issue :
6
Database :
Directory of Open Access Journals
Journal :
PLoS Genetics
Publication Type :
Academic Journal
Accession number :
edsdoj.7e591bf2c134b2397029f0d37644e88
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pgen.1009603