Back to Search
Start Over
b3galt6 Knock-Out Zebrafish Recapitulate β3GalT6-Deficiency Disorders in Human and Reveal a Trisaccharide Proteoglycan Linkage Region.
- 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