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
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
Figures
Figure Gallery (8 images)
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
b3galt6b3galt6cmg20/cmg20standard conditionsAdultRTPCR
b3galt6WTstandard conditionsAdultRTPCR
1 - 2 of 2
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Phenotype
Fish Conditions Stage Phenotype Figure
b3galt6cmg20/cmg20standard conditionsDays 14-20
b3galt6cmg20/cmg20standard conditionsDays 14-20
b3galt6cmg20/cmg20standard conditionsDays 14-20
b3galt6cmg20/cmg20standard conditionsDays 14-20
b3galt6cmg20/cmg20standard conditionsDays 14-20
b3galt6cmg20/cmg20standard conditionsDays 14-20
b3galt6cmg20/cmg20standard conditionsDays 14-20
b3galt6cmg20/cmg20standard conditionsDays 14-20
b3galt6cmg20/cmg20standard conditionsDays 14-20
b3galt6cmg20/cmg20standard conditionsAdult
1 - 10 of 49
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cmg20
    		Indel
    cmg22
      		Small Deletion
      1 - 2 of 2
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      Human Disease / Model
      Human Disease Fish Conditions Evidence
      Ehlers-Danlos syndromeb3galt6cmg20/cmg20standard conditionsTAS
      Ehlers-Danlos syndromeb3galt6cmg22/cmg22standard conditionsTAS
      1 - 2 of 2
      Show
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      b3galt6CRISPR3-b3galt6CRISPR
      b3galt6CRISPR4-b3galt6CRISPR
      b3galt6CRISPR5-b3galt6CRISPR
      1 - 3 of 3
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      Fish
      Fish
      b3galt6cmg20/cmg20
      b3galt6cmg22/cmg22
      WT
      1 - 3 of 3
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      Antibodies
      No data available
      Orthology
      No data available
      Engineered Foreign Genes
      No data available
      Mapping
      No data available
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      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.