Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations

Key Points The extracellular matrices (ECMs) of connective tissues are crucial for normal development and tissue function, and mutations in ECM genes result in a wide range of serious inherited disorders. These include skeletal dysplasias, such osteogenesis imperfecta, and a spectrum of chondrodysplasias, Ehlers–Danlos syndrome, forms of muscular dystrophy, epidermolysis bullosa and Alport syndrome Mutations cause ECM dysfunction by several mechanisms. First, secretion of ECM components can be reduced by mutations affecting synthesis or structural mutations causing cellular retention and/or degradation. The secretion of mutant proteins can also disturb crucial interactions with consequent effects on structure and stability of the ECM. Recent experiments also show that mutant misfolded extracellular matrix proteins such as cartilage oligomeric protein (COMP), collagens and matrilin 3 induce significant endoplasmic reticulum (ER) stress, and trigger the unfolded protein response (UPR). UPR can lead to deleterious downstream consequences, such as apoptosis and altered gene expression, and this can contribute to the molecular pathology of the mutations. The emerging importance of ER stress in the pathology of a range of connective tissue disorders offers the possibility of new treatment strategies. These strategies target ER stress and seek to manipulate this pathway by reducing either the mutant protein load or the deleterious cellular consequences of ER-stress. The pathophysiology of the many inherited connective tissue disorders resulting from ECM protein misfolding mutations most probably results from the combined effects of the extracellular consequences of reduced or abnormal protein on matrix structure and function, and the cellular consequences of ER stress. Mutations that affect the extracellular matrix (ECM) cause a range of inherited diseases. As well as exerting effects outside the cell, increasing evidence suggests that misfolded mutant proteins can cause stress inside cells, which contributes to disease pathology. Tissue-specific extracellular matrices (ECMs) are crucial for normal development and tissue function, and mutations in ECM genes result in a wide range of serious inherited connective tissue disorders. Mutations cause ECM dysfunction by combinations of two mechanisms. First, secretion of the mutated ECM components can be reduced by mutations affecting synthesis or by structural mutations causing cellular retention and/or degradation. Se