Molecular characterization of beta 1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS)

Catherine Bui, Ibtissam Talhaoui, Matthieu Chabel, Guillermo Mulliert, Michael W. H. Coughtrie, Mohamed Ouzzine, Sylvie Fournel-Gigleux

    Research output: Contribution to journalArticle

    16 Citations (Scopus)

    Abstract

    beta 1,4-Galactosyltransferase 7 (beta 4GalT7) is a key enzyme initiating glycosaminoglycan (GAG) synthesis. Based on in vitro and ex vivo kinetics studies and structure-based modelling, we molecularly characterized beta 4GalT7 mutants linked to the progeroid form of Ehlers-Danlos syndrome (EDS), a severe connective tissue disorder. Our results revealed that loss of activity upon L206P substitution due to altered protein folding is the primary cause for the GAG synthesis defect in patients carrying the compound A186D and L206P mutations. We showed that R270C substitution strongly reduced beta 4GalT7 affinity towards xyloside acceptor, thus affecting GAG chains formation. This study establishes the molecular basis for beta 4GalT7 defects associated with altered GAG synthesis in EDS. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

    Original languageEnglish
    Pages (from-to)3962-3968
    Number of pages7
    JournalFEBS Letters
    Volume584
    Issue number18
    DOIs
    Publication statusPublished - 24 Sep 2010

    Keywords

    • Ehlers-Danlos syndrome
    • Point mutation
    • Galactosyltransferase defect
    • Glycosaminoglycan synthesis
    • Congenital glycosyltransferase disorder
    • Galactosyltransferase-I beta4GalT-7
    • Heparan sulfate
    • Protein
    • Biosynthesis
    • Proteoglycan
    • Fibroblasts
    • Expression
    • Patient
    • Binding
    • Identification

    Cite this

    Bui, C., Talhaoui, I., Chabel, M., Mulliert, G., Coughtrie, M. W. H., Ouzzine, M., & Fournel-Gigleux, S. (2010). Molecular characterization of beta 1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS). FEBS Letters, 584(18), 3962-3968. https://doi.org/10.1016/j.febslet.2010.08.001
    Bui, Catherine ; Talhaoui, Ibtissam ; Chabel, Matthieu ; Mulliert, Guillermo ; Coughtrie, Michael W. H. ; Ouzzine, Mohamed ; Fournel-Gigleux, Sylvie. / Molecular characterization of beta 1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS). In: FEBS Letters. 2010 ; Vol. 584, No. 18. pp. 3962-3968.
    @article{ee58420722084d78bd0e0e0f58f1e1f0,
    title = "Molecular characterization of beta 1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS)",
    abstract = "beta 1,4-Galactosyltransferase 7 (beta 4GalT7) is a key enzyme initiating glycosaminoglycan (GAG) synthesis. Based on in vitro and ex vivo kinetics studies and structure-based modelling, we molecularly characterized beta 4GalT7 mutants linked to the progeroid form of Ehlers-Danlos syndrome (EDS), a severe connective tissue disorder. Our results revealed that loss of activity upon L206P substitution due to altered protein folding is the primary cause for the GAG synthesis defect in patients carrying the compound A186D and L206P mutations. We showed that R270C substitution strongly reduced beta 4GalT7 affinity towards xyloside acceptor, thus affecting GAG chains formation. This study establishes the molecular basis for beta 4GalT7 defects associated with altered GAG synthesis in EDS. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.",
    keywords = "Ehlers-Danlos syndrome, Point mutation, Galactosyltransferase defect, Glycosaminoglycan synthesis, Congenital glycosyltransferase disorder, Galactosyltransferase-I beta4GalT-7, Heparan sulfate, Protein, Biosynthesis, Proteoglycan, Fibroblasts, Expression, Patient, Binding, Identification",
    author = "Catherine Bui and Ibtissam Talhaoui and Matthieu Chabel and Guillermo Mulliert and Coughtrie, {Michael W. H.} and Mohamed Ouzzine and Sylvie Fournel-Gigleux",
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    Bui, C, Talhaoui, I, Chabel, M, Mulliert, G, Coughtrie, MWH, Ouzzine, M & Fournel-Gigleux, S 2010, 'Molecular characterization of beta 1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS)', FEBS Letters, vol. 584, no. 18, pp. 3962-3968. https://doi.org/10.1016/j.febslet.2010.08.001

    Molecular characterization of beta 1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS). / Bui, Catherine; Talhaoui, Ibtissam; Chabel, Matthieu; Mulliert, Guillermo; Coughtrie, Michael W. H.; Ouzzine, Mohamed; Fournel-Gigleux, Sylvie.

    In: FEBS Letters, Vol. 584, No. 18, 24.09.2010, p. 3962-3968.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Molecular characterization of beta 1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS)

    AU - Bui, Catherine

    AU - Talhaoui, Ibtissam

    AU - Chabel, Matthieu

    AU - Mulliert, Guillermo

    AU - Coughtrie, Michael W. H.

    AU - Ouzzine, Mohamed

    AU - Fournel-Gigleux, Sylvie

    PY - 2010/9/24

    Y1 - 2010/9/24

    N2 - beta 1,4-Galactosyltransferase 7 (beta 4GalT7) is a key enzyme initiating glycosaminoglycan (GAG) synthesis. Based on in vitro and ex vivo kinetics studies and structure-based modelling, we molecularly characterized beta 4GalT7 mutants linked to the progeroid form of Ehlers-Danlos syndrome (EDS), a severe connective tissue disorder. Our results revealed that loss of activity upon L206P substitution due to altered protein folding is the primary cause for the GAG synthesis defect in patients carrying the compound A186D and L206P mutations. We showed that R270C substitution strongly reduced beta 4GalT7 affinity towards xyloside acceptor, thus affecting GAG chains formation. This study establishes the molecular basis for beta 4GalT7 defects associated with altered GAG synthesis in EDS. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

    AB - beta 1,4-Galactosyltransferase 7 (beta 4GalT7) is a key enzyme initiating glycosaminoglycan (GAG) synthesis. Based on in vitro and ex vivo kinetics studies and structure-based modelling, we molecularly characterized beta 4GalT7 mutants linked to the progeroid form of Ehlers-Danlos syndrome (EDS), a severe connective tissue disorder. Our results revealed that loss of activity upon L206P substitution due to altered protein folding is the primary cause for the GAG synthesis defect in patients carrying the compound A186D and L206P mutations. We showed that R270C substitution strongly reduced beta 4GalT7 affinity towards xyloside acceptor, thus affecting GAG chains formation. This study establishes the molecular basis for beta 4GalT7 defects associated with altered GAG synthesis in EDS. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

    KW - Ehlers-Danlos syndrome

    KW - Point mutation

    KW - Galactosyltransferase defect

    KW - Glycosaminoglycan synthesis

    KW - Congenital glycosyltransferase disorder

    KW - Galactosyltransferase-I beta4GalT-7

    KW - Heparan sulfate

    KW - Protein

    KW - Biosynthesis

    KW - Proteoglycan

    KW - Fibroblasts

    KW - Expression

    KW - Patient

    KW - Binding

    KW - Identification

    U2 - 10.1016/j.febslet.2010.08.001

    DO - 10.1016/j.febslet.2010.08.001

    M3 - Article

    VL - 584

    SP - 3962

    EP - 3968

    JO - FEBS Letters

    JF - FEBS Letters

    SN - 0014-5793

    IS - 18

    ER -