The autosomal, recessively inherited,
adducted thumb-clubfoot syndrome (ATCS) represents a generalized connective tissue disorder with congenital malformations,
contractures of thumbs and feet, and a typical facial appearance. Cognitive development is normal in ATCS patients during childhood. ATCS is caused by homozygous nonsense and missense mutations in CHST14 which encodes an N-
acetylgalactosamine 4-O-sulfotransferase 1 (D4ST1) that catalyzes the 4-O-sulfation of N-
acetylgalactosamine in the repeating iduronic acid-alpha-1,3-N-acetylgalactosamine
disaccharide sequence to form
dermatan sulfate (DS). ATCS mutations lead to either a decrease or a loss of D4ST1 activity, as revealed by absence of DS and an excess of
chondroitin sulfate (CS) in patient's fibroblasts. Either of these effects or their combination might cause the observed clinical symptoms by altering the physiological pattern of dermatan and CS chains on their corresponding
proteoglycans (PGs). ATCS is the only recognized disorder resulting from a defect that is specific to DS biosynthesis, and thus represents another class of the congenital glycosylation disorders.
Congenital disorders of glycosylation (CDG) include all
genetic diseases that result from defects in the synthesis of
glycans. These disorders cause a wide range of human diseases, with examples emanating from all medical subspecialties. ATCS is the first human disorder that emphasizes a role for DS in human development and extracellular matrix maintenance.