Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement.
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.
Thiele
Holger
H
Institute of Medical Genetics, Charité University Hospital, Humboldt University, Berlin 13353, Germany.
Sakano
Masahiro
M
Kitagawa
Hiroshi
H
Sugahara
Kazuyuki
K
Rajab
Anna
A
Höhne
Wolfgang
W
Ritter
Heide
H
Leschik
Gundula
G
Nürnberg
Peter
P
Mundlos
Stefan
S
D001665:Binding Sites; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D008954:Models, Biological; D010009:Osteochondrodysplasias / Q000209:etiology*; D013122:Spinal Diseases / Q000209:etiology*; D015238:Sulfotransferases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000097811:Carbohydrate Sulfotransferases
D015238:Sulfotransferases; D000097811:Carbohydrate Sulfotransferases