Given the central role of the ER in the synthesis of proteins for the entire exocytic and endocytic pathways, it is not surprising that many inherited diseases are a direct consequence of proteins failing to pass ER quality control. Many metabolic disorders, including some lysosomal storage diseases, are a direct consequence of key enzymes failing to be exported from the ER. The most common form of cystic fibrosis is due to the inability of cells to export a mutant form of the cystic fibrosis transmembrane regulator to the cell surface, where it would normally function as a chloride channel for the respiratory system and pancreas. Similarly, the inability of the liver to secrete mutated forms of a1- antitrypsin predisposes to the lung dis-ease emphysema. Normally, a1-antitrypsinprotects tissues by inhibiting extracellular proteases such as elastase, which is produced by neutrophils. Mutations prevent a1-antitrypsinfolding in the ER, resulting in its degradation. The resulting deficiency in a1-antitrypsin circulating in the blood allows elastase to destroy lung tissue, leading to emphysema. In severe cases, mutant forms of the protein not only fail to be exported from the ER but also elude degradation path-ways, accumulating as insoluble aggregates that induce stress responses and liver failure.
In some conditions, the ER uses the unfolded protein response to compensate, in part, for mutations in cargo proteins. In congenital hypothyroidism, mutant thyroglobulin is not exported efficiently from the ER. Excess protein accumulates as in soluble aggregates in the ER. Feedback pathways trigger massive proliferation of ER in an attempt to produce normal levels of circulating hormone. Similarly, in mild forms of osteogenesis imperfecta, osteoblasts assemble and secrete defective procollagen chains for bone synthesis, even though the resulting bone tissue is weak. 'The alternative, complete loss of procollagen by retention and degradation of the mutant procollagen in the ER would be lethal. Faulty ER quality control may also contribute to diseases of the central and peripheral nervous systems, including Alzheimer's disease.