English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  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.

Item is

Basic

show hide
Genre: Journal Article
Alternative Title : Proc Natl Acad Sci USA

Files

show Files

Locators

show

Creators

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

Content

show
hide
Free keywords: -
 Abstract: 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.

Details

show
hide
Language(s): eng - English
 Dates: 2004-07-06
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: eDoc: 228878
DOI: 10.1073/pnas.0400334101
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Proceedings of the National Academy of Sciences
  Alternative Title : Proc Natl Acad Sci USA
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 101 (27) Sequence Number: - Start / End Page: 10155 - 10160 Identifier: ISSN: 0027-8424