Universität zu Köln

Pottie, Lore ORCID: 0000-0001-5102-975X, Van Gool, Wouter, Vanhooydonck, Michiel ORCID: 0000-0001-7350-9009, Hanisch, Franz-Georg, Goeminne, Geert, Rajkovic, Andreja ORCID: 0000-0003-1062-0564, Coucke, Paul, Sips, Patrick ORCID: 0000-0001-9241-5980 and Callewaert, Bert ORCID: 0000-0002-9743-4205 (2021). Loss of zebrafish atp6v1e1b, encoding a subunit of vacuolar ATPase, recapitulates human ARCL type 2C syndrome and identifies multiple pathobiological signatures. PLoS Genet., 17 (6). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7404

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Abstract

Author summary Cutis laxa syndromes are pleiotropic disorders of the connective tissue, characterized by skin redundancy and variable systemic manifestations. Cutis laxa syndromes are caused by pathogenic variants in genes encoding structural and regulatory components of the extracellular matrix or in genes encoding components of cellular trafficking, metabolism, and mitochondrial function. Pathogenic variants in genes coding for vacuolar-ATPases, a multisubunit complex responsible for the acidification of multiple intracellular vesicles, cause type 2 cutis laxa syndromes, a group of cutis laxa subtypes further characterized by neurological, skeletal, and rarely cardiopulmonary manifestations. To investigate the pathomechanisms of vacuolar-ATPase dysfunction, we generated zebrafish models that lack a crucial subunit of the vacuolar-ATPases. The mutant zebrafish models show morphological and functional features reminiscent of the phenotypic manifestations in cutis laxa patients carrying pathogenic variants in ATP6V1E1. In-depth analysis at multiple -omic levels identified biological signatures that indicate impairment of signaling pathways, lipid metabolism, and mitochondrial respiration. We anticipate that these data will contribute to a better understanding of the pathogenesis of cutis laxa syndromes and other disorders involving defective v-ATPase function, which may eventually improve patient treatment and management. 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pottie, Lore UNSPECIFIED orcid.org/0000-0001-5102-975X UNSPECIFIED Van Gool, Wouter UNSPECIFIED UNSPECIFIED UNSPECIFIED Vanhooydonck, Michiel UNSPECIFIED orcid.org/0000-0001-7350-9009 UNSPECIFIED Hanisch, Franz-Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Goeminne, Geert UNSPECIFIED UNSPECIFIED UNSPECIFIED Rajkovic, Andreja UNSPECIFIED orcid.org/0000-0003-1062-0564 UNSPECIFIED Coucke, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Sips, Patrick UNSPECIFIED orcid.org/0000-0001-9241-5980 UNSPECIFIED Callewaert, Bert UNSPECIFIED orcid.org/0000-0002-9743-4205 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-584092
DOI:	10.1371/journal.pgen.1009603
Journal or Publication Title:	PLoS Genet.
Volume:	17
Number:	6
Date:	2021
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1553-7404
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RENAL TUBULAR-ACIDOSIS; MENTAL-RETARDATION; LYSOSOMAL PH; V-ATPASE; KEY ROLE; MUTATIONS; PATHWAY; PROTEIN; GENE; INTERNALIZATION Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58409