Skeletal Dysplasias Caused by Defects in Glycosaminoglycan Sulfation

Among the large number of skeletal conditions, there is a group associated with defects in the sulfation of macromolecules. Sulfate metabolism plays important roles in the development and function of different tissues and organs. In cartilage tissue, proteoglycans (PGs) are the most abundant macromolecules of the extracellular matrix. PGs are composed by a core protein to which, linear aminopolysaccharide chains (glycosaminoglycans, GAGs) are covalently bound. GAGs can be heavily sulfated, and the sulfate groups are fundamental, as they confer specific physico-chemical properties (charge and hydrophilicity) to PGs and in addition assure the interactions with other extracellular matrix molecules as well as with growth factors regulating tissue structure, mechanical properties, and cell behavior. To assure PG sulfation, chondrocytes mostly exploit sulfate from the extracellular environment, which is taken up and activated in the cytosol to 3′-phosphoadenosine 5′-phosphosulfate, the universal sulfate donor, used in sulfotransferase reactions. This chapter presents an overview of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in glycosaminoglycan sulfation. Future research in these dysplasias will hopefully contribute to the deep understanding of the disease pathogenesis in order to allow for the development of targeted pharmacological treatment to alleviate, modify, or prevent the disease progression.