PUBLICATION
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, J.W., Alluyn, L., Gistelinck, C., Syx, D., Salmon, P.L., Coucke, P.J., Larson, G., Yamada, S., Willaert, A., Malfait, F.
- ID
- ZDB-PUB-201229-37
- Date
- 2020
- Source
- Frontiers in cell and developmental biology 8: 597857 (Journal)
- Registered Authors
- Coucke, Paul, Willaert, Andy
- Keywords
- b3galt6, linkeropathies, proteoglycans, trisaccharide linkage region, zebrafish
- MeSH Terms
- none
- PubMed
- 33363150 Full text @ Front Cell Dev Biol
Citation
Delbaere, S., De Clercq, A., Mizumoto, S., Noborn, F., Bek, J.W., Alluyn, L., Gistelinck, C., Syx, D., Salmon, P.L., Coucke, P.J., Larson, G., Yamada, S., Willaert, A., Malfait, F. (2020) b3galt6 Knock-Out Zebrafish Recapitulate β3GalT6-Deficiency Disorders in Human and Reveal a Trisaccharide Proteoglycan Linkage Region. Frontiers in cell and developmental biology. 8:597857.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping