Spondyloepiphyseal dysplasia, Omani type: Further definition of the phenotype

Abstract

Spondyloepiphyseal dysplasia (SED), Omani type (OMIM 608637) is a recessively inherited skeletal dysplasia previously described in two distantly related families from the Republic of Oman. The phenotype consists of short stature, severe kyphoscoliosis, arthritic joints (elbows, wrists, knees), secondary large joint dislocations, rhizomelia, fusion of carpal bones and mild brachydactyly. Affected individuals were homozygous for a missense mutation, R304Q in CHST3 that encodes the enzyme chondroitin 6-O-sulfotransferase-1 (C6ST-1). This enzyme mediates the sulfation of proteoglycans, particularly chondroitin sulfate (CS), in the extracellular matrix of cartilage. Here we describe the identification of a mutation (857T > C predicting the substitution L286P) in CHST3 in a Turkish family and extend the clinical phenotype of SED-Omani type to include congenital joint dislocation, club feet, ventricular septal defect, deafness, metacarpal shortening and accessory carpal ossification centers. Fibroblasts and urine obtained from affected patients demonstrated negligible levels of 6-O-sulfated GalNAc residue in CS. Furthermore, the 6-O-sulfotransferase activity of cloned C6ST-1 into which the L286P mutation had been introduced was dramatically reduced, confirming the pathogenicity of this substitution. These results indicate that the clinical consequences of a deficiency of 6-O-sulfation in CS can be varied and that a clinical spectrum may exist similar to that seen in other skeletal dysplasias characterized by disorders of proteoglycan sulfation.

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.…”

Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

“…Biochemical analysis showed the majority of these mutations result in loss-of-function or severe reduction in the enzymatic activity (31,(33)(34)(35)(36). Recessive inheritance would be consistent with most rare mutations that affect enzymes.…”

“…Rare mutations in CHST3 that disrupt its enzymatic activity have been reported in patients with recessive skeletal abnormalities, including spondyloepiphyseal dysplasia Omani type, Larsen syndrome, humerospinal dysostosis, and chondrodysplasia with multiple dislocation (31)(32)(33)(34)(35)(36). Despite the different diagnostic labels, patients with CHST3 mutations have similar clinical characteristics and can be generally classified as spondyloepiphyseal dysplasia with congenital joint dislocation and vertebral changes as the principal features (OMIM 603799).…”

Genetics and pathophysiology of mammalian sulfate biology

“…and CHST3 sulfotransferase genes is proposed to be a consequence of reduced sulfate content of glycosaminoglycans which impairs extracellular collagen bundling and function (van Roij et al, 2008;Miyake et al, 2013). The endogenously generated sulfur-containing gases H2S and SO2 that are intermediates of the sulfate generating pathways (Fig.…”