Disorders of intracellular protein trafficking in human disease

Most known forms of osteogenesis imperfecta (OI) are caused by mutations in type I collagen genes. The numerous mutations described to date result in either decreased synthesis of normal collagen molecules or synthesis of aberrant molecules. The aberrant molecules are in some cases secreted into the medium, but in many cases they are retained intracellularly. The heterogeneity of molecular defects underlying OI, and the different fates and functional characteristics of the aberrant collagen molecules, emphasize the importance of understanding the intracellular trafficking of normal and abnormal forms of collagen. A detailed knowledge of the biogenesis of each mutated form of collagen is essential to explain the whole range of clinical manifestations of the disease and to search for possible therapies based on the ability to manipulate the intracellular transport of newly synthesized proteins. The purpose of this article is to briefly summarize observations on the biogenesis of proteins in the secretory pathway, especially as they relate to human disease. Given the generality of the cellular processes that control protein trafficking, these observations could prove useful in analyses of the pathogenesis of OI.