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b3galt6 knock-out zebrafish recapitulate β3GalT6-deficiency disorders in human and reveal a trisaccharide proteoglycan linkage region

Author
Organization
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.
Keywords
b3galt6, zebrafish, trisaccharide linkageregion, proteoglycans, linkeropathies

Citation

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MLA
Delbaere, Sarah, et al. “B3galt6 Knock-out Zebrafish Recapitulate Β3GalT6-Deficiency Disorders in Human and Reveal a Trisaccharide Proteoglycan Linkage Region.” BioRxiv, 2020, doi:10.1101/2020.06.22.165316.
APA
Delbaere, S., De Clercq, A., Mizumoto, S., Noborn, F., Bek, J. W., Alluyn, L., … Malfait, F. (2020). b3galt6 knock-out zebrafish recapitulate β3GalT6-deficiency disorders in human and reveal a trisaccharide proteoglycan linkage region. bioRxiv. https://doi.org/10.1101/2020.06.22.165316
Chicago author-date
Delbaere, Sarah, Adelbert De Clercq, Shuji Mizumoto, Fredrik Noborn, Jan Willem Bek, Lien Alluyn, Charlotte Gistelinck, et al. 2020. “B3galt6 Knock-out Zebrafish Recapitulate Β3GalT6-Deficiency Disorders in Human and Reveal a Trisaccharide Proteoglycan Linkage Region.” BioRxiv. https://doi.org/10.1101/2020.06.22.165316.
Chicago author-date (all authors)
Delbaere, Sarah, Adelbert De Clercq, Shuji Mizumoto, Fredrik Noborn, Jan Willem Bek, Lien Alluyn, Charlotte Gistelinck, Delfien Syx, Phil L. Salmon, Paul Coucke, Göran Larson, Shuhei Yamada, Andy Willaert, and Fransiska Malfait. 2020. “B3galt6 Knock-out Zebrafish Recapitulate Β3GalT6-Deficiency Disorders in Human and Reveal a Trisaccharide Proteoglycan Linkage Region.” BioRxiv. doi:10.1101/2020.06.22.165316.
Vancouver
1.
Delbaere S, De Clercq A, Mizumoto S, Noborn F, Bek JW, Alluyn L, et al. b3galt6 knock-out zebrafish recapitulate β3GalT6-deficiency disorders in human and reveal a trisaccharide proteoglycan linkage region. bioRxiv. 2020.
IEEE
[1]
S. Delbaere et al., “b3galt6 knock-out zebrafish recapitulate β3GalT6-deficiency disorders in human and reveal a trisaccharide proteoglycan linkage region,” bioRxiv. 2020.
@misc{8671756,
  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.}},
  author       = {{Delbaere, Sarah and De Clercq, Adelbert and Mizumoto, Shuji and Noborn, Fredrik and Bek, Jan Willem and Alluyn, Lien and Gistelinck, Charlotte and Syx, Delfien and Salmon, Phil L. and Coucke, Paul and Larson, Göran and Yamada, Shuhei and Willaert, Andy and Malfait, Fransiska}},
  keywords     = {{b3galt6,zebrafish,trisaccharide linkageregion,proteoglycans,linkeropathies}},
  language     = {{eng}},
  series       = {{bioRxiv}},
  title        = {{b3galt6 knock-out zebrafish recapitulate β3GalT6-deficiency disorders in human and reveal a trisaccharide proteoglycan linkage region}},
  url          = {{http://dx.doi.org/10.1101/2020.06.22.165316}},
  year         = {{2020}},
}

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