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  Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement

Thiele, H., Sakano, M., Kitagawa, H., Sugahara, K., Rajab, A., Höhne, W., et al. (2004). Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. Proceedings of the National Academy of Sciences, 101(27), 10155-10160. doi:10.1073/pnas.0400334101.

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Genre: Zeitschriftenartikel
Alternativer Titel : Proc Natl Acad Sci USA

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 Urheber:
Thiele, Holger, Autor
Sakano, Masahiro, Autor
Kitagawa, Hiroshi, Autor
Sugahara, Kazuyuki, Autor
Rajab, Anna, Autor
Höhne, Wolfgang, Autor
Ritter, Heide, Autor
Leschik, Gundula, Autor
Nürnberg, Peter, Autor
Mundlos, Stefan1, Autor           
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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 Zusammenfassung: We studied two large consanguineous families from Oman with a distinct form of spondyloepiphyseal dysplasia (SED Omani type). By using a genome-wide linkage approach, we were able to map the underlying gene to a 4.5-centimorgan interval on chromosome 10q23. We sequenced candidate genes from the region and identified a missense mutation in the chondroitin 6-O-sulfotransferase (C6ST-1) gene (CHST3) changing an arginine into a glutamine (R304Q) in the well conserved 3'-phosphoadenosine 5'-phosphosulfate binding site. C6ST-1 catalyzes the modifying step of chondroitin sulfate (CS) synthesis by transferring sulfate to the C-6 position of the N-acetylgalactosamine of chondroitin. From the crystal structures of other sulfotransferases, it could be inferred that Arg-304 is essential for the structure of the cosubstrate binding site. We used recombinant C6ST-1 to show that the identified missense mutation completely abolishes C6ST-1 activity. Disaccharide composition analysis of CS chains by anion-exchange HPLC shows that both {Delta}HexA-GalNAc(6S) and {Delta}HexA(2S)-GalNAc(6S) were significantly reduced in the patient's cells and that {Delta}HexA-GalNAc(4S,6S), undetectable in controls, was elevated. Analysis of the patient's urine shows marked undersulfation of CS, in particular reduction in 6-O-sulfated disaccharide and an increase in the nonsulfated unit. Our results indicate that the mutation in CHST3 described here causes a specific but generalized defect of CS chain sulfation resulting in chondrodysplasia with major involvement of the spine.

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Sprache(n): eng - English
 Datum: 2004-07-06
 Publikationsstatus: Erschienen
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 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: eDoc: 228878
DOI: 10.1073/pnas.0400334101
 Art des Abschluß: -

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Titel: Proceedings of the National Academy of Sciences
  Alternativer Titel : Proc Natl Acad Sci USA
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 101 (27) Artikelnummer: - Start- / Endseite: 10155 - 10160 Identifikator: ISSN: 0027-8424