Collagen II Mutations in Inherited Cartilage Disease: Our Current Understanding of Genotype-Phenotype Correlations

Cartilage contains chondrocytes embedded in a complex extracellular matrix rich in collagen II fibrils that provide the structural framework for other cartilage components such as aggrecan, matrilins 1 and 3, COMP, decorin, fibromodulin, and minor collagens type IX and XI. The central role of the collagen II fibrils is reflected in the large number of mutations in the gene encoding collagen II (COL2A1), that cause chondrodysplasias, ranging from premature arthritis through to severe early lethal disorders. Mutations that reduce synthesis of structurally normal protein cause Stickler syndrome, type I, at the milder end of the COL2A1 chondrodysplasia clinical spectrum. Structural mutations most often cause more severe phenotypes, achondrogenesis/hypochondrogenesis, due to their impacts on procollagen II folding, stability, secretion, and in some cases altered interactions. These are commonly missense mutations, predominantly substitutions for glycine residues in the triple helix. Arginine to cysteine mutations in the helix are generally less severe than glycine substitutions, although p.R989C is a notable exception, causing a severe spondyloepiphyseal dysplasia. How mutant procollagen II engages with the intracellular ER quality control machinery, and if the unfolded/misfolded procollagen elicits an unfolded protein response, is not resolved and awaits further experimentation. Restoring proteostasis by stimulating mutant protein degradation, improving mutant protein folding with chemical chaperones, or modulating unfolded protein response signaling with small molecules offers hope for treating genetic collagen II disorders.