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b3galt6 Knock-Out Zebrafish Recapitulate β3GalT6-Deficiency Disorders in Human and Reveal a Trisaccharide Proteoglycan Linkage Region.

Authors :
Delbaere S
De Clercq A
Mizumoto S
Noborn F
Bek JW
Alluyn L
Gistelinck C
Syx D
Salmon PL
Coucke PJ
Larson G
Yamada S
Willaert A
Malfait F
Source :
Frontiers in cell and developmental biology [Front Cell Dev Biol] 2020 Dec 10; Vol. 8, pp. 597857. Date of Electronic Publication: 2020 Dec 10 (Print Publication: 2020).
Publication Year :
2020

Abstract

Proteoglycans are structurally and functionally diverse biomacromolecules found abundantly on cell membranes and in the extracellular matrix. They consist of a core protein linked to glycosaminoglycan chains via a tetrasaccharide linkage region. Here, we show that CRISPR/Cas9-mediated b3galt6 knock-out zebrafish, lacking galactosyltransferase II, which adds the third sugar in the linkage region, largely recapitulate the phenotypic abnormalities seen in human β3GalT6-deficiency disorders. These comprise craniofacial dysmorphism, generalized skeletal dysplasia, skin involvement and indications for muscle hypotonia. In-depth TEM analysis revealed disturbed collagen fibril organization as the most consistent ultrastructural characteristic throughout different affected tissues. Strikingly, despite a strong reduction in glycosaminoglycan content, as demonstrated by anion-exchange HPLC, subsequent LC-MS/MS analysis revealed a small amount of proteoglycans containing a unique linkage region consisting of only three sugars. This implies that formation of glycosaminoglycans with an immature linkage region is possible in a pathogenic context. Our study, therefore unveils a novel rescue mechanism for proteoglycan production in the absence of galactosyltransferase II, hereby opening new avenues for therapeutic intervention.<br />Competing Interests: PS was employed by the company Bruker MicroCT. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (Copyright © 2020 Delbaere, De Clercq, Mizumoto, Noborn, Bek, Alluyn, Gistelinck, Syx, Salmon, Coucke, Larson, Yamada, Willaert and Malfait.)

Details

Language :
English
ISSN :
2296-634X
Volume :
8
Database :
MEDLINE
Journal :
Frontiers in cell and developmental biology
Publication Type :
Academic Journal
Accession number :
33363150
Full Text :
https://doi.org/10.3389/fcell.2020.597857