Recessively inherited, late onset spondylar dysplasia and peripheral corneal opacity with anomalies in urinary mucopolysaccharides: A possible error of chondroitin‐6‐sulfate synthesis

Toledo, S. P. A.; Pa, Mourão; Lamego, C; Ca, Alves; Cp, Dietrich; Lm, Assis; Mattar, E

doi:10.1002/ajmg.1320020408

Cited by 38 publications

(21 citation statements)

References 21 publications

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“…In patients with the Toledo subtype (OMIM 271630) of this dysplasia, an undersulfated chondroitin 6-O-sulfate (CS-C) was shown to be excreted in the urine, suggesting a possible defect in a chondroitin sulfotransferase (22). In particular, a high proportion of nonsulfated disaccharides, an abnormally low proportion of 6-O-sulfated disaccharides of the CS chains in the urine, and a low sulfotransferase activity in the serum were detected.…”

Section: Discussionmentioning

confidence: 99%

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

Thiele

Sakano

Kitagawa

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

175

143

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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 ⌬HexA-GalNAc(6S) and ⌬HexA(2S)-GalNAc(6S) were significantly reduced in the patient's cells and that ⌬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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Section: Discussionmentioning

confidence: 99%

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

Thiele

Sakano

Kitagawa

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

175

143

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“…As expected, a more detailed clinical examination of the affected patients showed slightly shorter legs, moderate shortness of the trunk and neck, and increased width of the distal ends of the long bones. These clinical observations are more prominent at the femoral necks, which are short and broad; at the knees, which show a moderate broadness of the metaphyses; and at the vertebral column, which shows a generalized platyspondyly, irregular vertebral plates, and reduced intervertebral spaces (17).…”

Section: % 84%mentioning

confidence: 96%

Distribution of chondroitin 4–sulfate and chondroitin 6–sulfate in human articular and growth cartilage

Mourāo

1988

Arthritis & Rheumatism

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The relative concentrations of chondroitin 4-and chondroitin &sulfate in different normal human cartilages are reported. Articular cartilages contained higher concentrations of chondroitin &sulfate, whereas growth cartilages contained nearly equal amounts of chondroitin 4-and chondroitin 6sulfate. Adult cartilages, in which the calcification process is already complete, contained only chondroitin &sulfate. The results suggest that chondroitin h u l f a t e is related to the integrity of the articular surfaces, whereas chondroitin 4-sulfate seems to be an important factor in the calcification process. The pathogenesis of the bone and cartilage alterations that occur in patients affected by heritable disorders of the sulfation of chondroitin sulfate are discussed in view of these findings.The various functions of cartilages include providing frameworks that direct the growth of bones (growth cartilages) and providing a covering for the articular surfaces of bones (articular cartilages) in order to withstand compressive loads and to enable the bones to slide smoothly against each other. Among the macromolecular components of cartilages, both collagen and a component of the proteoglycan molecules (namely, glycosaminoglycan) are known to be responsible for the tensile strength and the resilience of the articular cartilages, and are known to be involved in the ossification process that occurs in the growth cartilages (1,2).In the last decade, several groups of workers have reported changes in the concentration of cartilaginous glycosaminoglycans under normal and pathologic conditions. For example, several authors have reported changes in the relative proportions of chondroitin 4-and chondroitin 6-sulfate in human epiphyseal cartilages with aging and arthrosis (3,4), differences in the molecular weight of chondroitin sulfates obtained from articular and subarticular cartilages (9, and an increase in the concentration of keratan sulfate in articular cartilage with aging (4,6).This report details the relative concentrations of chondroitin 4-and chondroitin 6-sulfate in different normal human cartilages obtained from infants and adults. The results allow an extensive discussion about modifications that occur in the cartilages of patients affected by heritable disorders of the biosynthesis of chondroitin sulfate. PATIENTS AND METHODS

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“…In contrast, human C6ST-1 exhibited abundant expression in the adult heart, placenta, skeletal muscle, and thymus and very little in adult lung and peripheral blood leukocytes (23). Furthermore, a deficiency in chondroitin 6-O-sulfotransferase activity is reportedly associated with a heritable form of spondyloepiphyseal dysplasia (27,28), suggesting that the chondroitin 6-O-sulfotransferase appears to be essential for normal skeletal development. Therefore, the products of the genes may not provide functional back-up in all cells.…”

Section: Table I Comparison Of Polymer Gag Acceptor Specificity Of C6mentioning

confidence: 99%

“…To verify this, we determined the levels of amplification of the glyceraldehyde-3-phosphate dehydrogenase, whose transcript is always present in the tissues at a constant level (17). Using the normalized cDNA input, we performed the amplification of a transcript, using a serial number of cycles (27,30, and 33 cycles) to find the conditions for a semiquantitative amplification. The best results were obtained by carrying out 30 cycles at 94°C for 30 s, 55°C for 30 s, and 72°C for 75 s in a total volume of 50 l using the 5Ј and 3Ј primers described above, which were designed to span the intron in the novel sulfotransferase gene to discriminate a PCR product amplified from cDNA from, if any, one amplified from contaminating genomic DNA.…”

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confidence: 99%

Molecular Cloning and Expression of a Novel Chondroitin 6-O-Sulfotransferase

Kitagawa

Fujita

Ito

et al. 2000

Journal of Biological Chemistry

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A novel human chondroitin 6-O-sulfotransferase, designated C6ST-2, was identified by BLAST analysis of expressed sequence tag using the sequence of a previously described human chondroitin 6-O-sulfotransferase (C6ST-1) as a probe. The new cDNA sequence revealed an open reading frame coding for a protein of 486 amino acids with a type II transmembrane protein topology. The amino acid sequence displayed 24% identity to the human C6ST-1, and the highest sequence identity was found in the COOH-terminal catalytic domain. The expression of a soluble recombinant form of the protein in COS-1 cells produced an active sulfotransferase with marked specificity for polymer chondroitin. In contrast, keratan sulfate and oligosaccharides containing the Gal␤1-4GlcNAc sequence, which are good acceptor substrates for the C6ST-1, hardly served as acceptors. The identification of the reaction product indicated that the enzyme is a novel chondroitin 6-Osulfotransferase (C6ST-2) that mainly transfers sulfate to N-acetylgalactosamine. The coding region of C6ST-2 was contained in a single exon and localized to chromosome Xp11. Northern blot analysis of human brain poly(A) ؉ RNA revealed a single transcript of 2.4 kilobase pairs. Reverse transcription-polymerase chain reaction analysis showed that C6ST-2 is developmentally regulated in various tissues with expression persisting through adulthood in the spleen. Thus, we demonstrated the redundancy in chondroitin 6-O-sulfotransferases capable of forming chondroitin 6-sulfate, which is important for understanding the mechanisms leading to specific changes in the sulfation profile of chondroitin sulfate chains in various tissues during development and malignant transformation.

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Recessively inherited, late onset spondylar dysplasia and peripheral corneal opacity with anomalies in urinary mucopolysaccharides: A possible error of chondroitin‐6‐sulfate synthesis

Cited by 38 publications

References 21 publications

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

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

Distribution of chondroitin 4–sulfate and chondroitin 6–sulfate in human articular and growth cartilage

Molecular Cloning and Expression of a Novel Chondroitin 6-O-Sulfotransferase

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