Spondyloepiphyseal dysplasia, Omani type: further definition of the phenotype.
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.
van Roij
Mirjam H H
MH
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
Mizumoto
Shuji
S
Yamada
Shuhei
S
Morgan
Tim
T
Tan-Sindhunata
M B
MB
Meijers-Heijboer
H
H
Verbeke
J I L M
JI
Markie
David
D
Sugahara
Kazuyuki
K
Robertson
Stephen P
SP
D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D003001:Cloning, Molecular; D003241:Consanguinity; D004187:Disaccharides / Q000652:urine; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D009850:Oman; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011859:Radiography; D013131:Spine / Q000002:abnormalities / Q000000981:diagnostic imaging; D015238:Sulfotransferases / Q000235:genetics* / Q000652:urine; D000097811:Carbohydrate Sulfotransferases
D004187:Disaccharides; D015238:Sulfotransferases; D000097811:Carbohydrate Sulfotransferases