Omani‐type spondyloepiphyseal dysplasia with cardiac involvement caused by a missense mutation in CHST3

Abstract

We describe a family with progressive skeletal dysplasia and severe spinal involvement, short stature, premature arthrosis and joint contractures diagnosed as spondyloepiphyseal dysplasia Omani type. Mutation analysis in CHST3, the gene encoding for the chondroitin 6-O-sulfotransferase-1 (C6ST-1), revealed a homozygous missense mutation (T141M) in exon 3 in all three affected members of the family. Using recombinant C6ST-1, we showed that the identified missense mutation results in a reduction of C6ST-1 activity to 24-29% of the wild type protein. In addition to the previously noted skeletal features, affected members of this family also had cardiac involvement including mitral, tricuspid and/or aortic regurgitations and type E brachydactyly.

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

“…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).…”

“…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.…”

Human Genetic Disorders Caused by Mutations in Genes Encoding Biosynthetic Enzymes for Sulfated Glycosaminoglycans

“…The original patients with Omani-type spondyloepiphyseal dysplasia caused by a missense mutation (R304Q) had a short stature; severe kyphoscoliosis; osteoarthritis in elbow, wrist, and knee joints; secondary dislocation of the large joints; rhizomelia; fusion of carpal bones; and mild brachydactyly (76,77). Several of their clinical features (including ventricular septal, mitral, and/or tricuspid defects; aortic regurgitations; deafness; and metacarpal shortening) differed significantly from the original description of the disease in Turkish siblings (T141M and L286P) (78,79). 6-O-Sulfation on GalNAc residues in CS chains was barely detected in fibroblasts and urine obtained from the patients (78).…”