Skeletal Disorders Linked to GAG Synthesis

Skeletal dysplasias (SD) are a group of rare disorders mainly characterized by cartilage and bone growth anomalies. A significant number of them, including chondrodysplasia with multiple dislocations (CMD), have been related to pathogenic variants in genes encoding proteins involved directly or indirectly in the proteoglycan (PG) biosynthesis. PGs are organic macromolecules composed of a core protein and one or several glycosaminoglycan side chains (GAGs), consisting in repetitive sulfated disaccharides forming the Heparan Sulfate, Chondroitin Sulfate, and Dermatan sulfate. PGs are abundantly expressed in the chondrocyte ExtraCellular Matrix (ECM). They play an important role in chondrocyte maturation and endochondral ossification as co-receptors for growth factors and ensuring the maintenance of mechanical proprieties of cartilage. However, the implication of PG biosynthesis defect in the CMD physiopathology is still poorly understood and a number of patients still remains with unidentified molecular bases. This review focuses on genetic and glycobiological studies of CMD associated with glycosaminoglycan biosynthesis defects and related animal models. A deep comprehension of the molecular mechanisms leading to those disorders, mostly through extensive phenotypic analyses of in vitro and/or in vivo models, is essential for the development of novel biomarkers for clinical screenings and innovative therapeutics for these diseases.