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

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 ⌬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.

Sulfation patterns of exogenous chondroitin sulfate affect chondrogenic differentiation of ATDC5 cells

“…These functions are closely associated with the sulfation patterns of the CS moieties. Moreover, mutations in the genes of sulfotransferases, active sulfate synthetase or nucleotide-sugar transporters, which are indispensable for the synthesis of CS, cause chondrodysplasia in mice and humans [9][10][11][12][13][14]. These findings confirm that the sulfation of CS plays a critical role in chondrogenic differentiation.…”

Chondroitin beta-1,4-N-acetylgalactosaminyltransferase-1 missense mutations are associated with neuropathies

“…12 However, to the best of our knowledge, the association with neurological disorders has never been reported. The present investigation did not prove that the heterozygous ChGn-1 mutations cause neuropathy in two patients.…”

“…9 Recently, it has been reported that a broad spectrum of skeletal dysplasias result from mutations causing undersulfation of chondroitin sulfate chains in humans and in mice. [10][11][12][13][14] In contrast, no association between CSPGs and human peripheral neuropathies has been reported to date.…”

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

“…To date, mutations in the three CHST3 [82], CHST6 [83], and CHST14 [84] sulfotransferase genes have been recognized in cases of spondyloepiphyseal dysplasia, macular corneal dystrophy, and Ehlers-Danlos syndrome musculocontractural type 1, respectively. The CHST3 sulfotransferase catalyzes the 6-Osulfation of GalNAc in chondroitin and dermatan sulfate, whereas CHST6 catalyzes the 6-O-sulfation of GlcNAc in keratin sulfate, and CHST14 the 4-O-sulfation of GalNAc in dermatan sulfate.…”