Endocrinopathies in the Family of Endoplasmic Reticulum (ER) Storage Diseases: Disorders of Protein Trafficking and the Role of ER Molecular Chaperones*

From the studies described in this review, it is clear that structural information dictates not only the functional properties of exportable proteins, but also their ability to be transported in the intracellular secretory pathway. In ERSDs, the precise nature of the defect determines both the severity of the phenotype and the mode of inheritance. To our knowledge, all genetically inherited ERSDs are attributable to mutations in the coding sequence of exportable proteins; thus far, with the exception of abetalipoproteinemia (see Section IV.D), no mutations in ER chaperones (other than those that scientists have genetically engineered) have been reported as the cause of spontaneous disease. The elevations of ER chaperones in ERSDs may differ between mutations, between tissues, between individual patients, and between different physiological states (i.e., such as before and after hormone replacement therapy) in the same patient. Thus, measurement of ER chaperone levels plays an important diagnostic role, but probably should not be used as the sole basis to classify these illnesses. Moreover, because mutant secretory proteins have been reported to occur in virtually every organ system, ERSDs are more readily classified at the cell biological level, by the responses of the cells that actually synthesize the secretory protein, rather than the hormone deficiency associated with the illness at the end-organ level. With these ideas in mind, we present a schematic view in Fig. 4. According to this schema, all ERSDs begin with ER retention of the affected proteins or their subunits. Mutants may then be divided into two groups: type A, where the biological activity is preserved although the protein is transport-deficient; and type B, where the mutant has no potential for functional activity. Both categories include both recessive and dominant mutations. The primary clinical difference between these two classes is that type A ERSDs may be amenable to therapies designed to down-regulate the quality control of ER export so that potentially functional molecules can escape the ER and reach their intended intracellular destination. In both types of ERSDs, in most cases, the retained mutant protein is efficiently degraded in the ER (subtypes A-I and B-I). In these cases, the predominant, global phenotypes involve the symptoms and signs of hormone deficiency. However, careful biochemical and cell biological studies reveal various abnormalities in glandular function, typically including the elevation of the levels of one or more ER chaperones. As described in Section I.C, such elevations are a consequence of chronic adaptation to the presence of unfolded mutant secretory protein (the synthesis of which is stimulated all the more by endocrine feedback loops). As described in Section III, the elevated chaperones appear to be integrally related to the ER retention as well as perhaps the ERAD process that removes the misfolded proteins. In these cases, the ER compartment may expand, but the secretory cells are likely to survive. In the more unusual subtype II (subtypes B-II and perhaps A-II), the mutant protein exhibits an intrinsic tendency to resist ERAD, creating a potentially dangerous accumulation of indigestible material (Fig. 4). This may be due to the unusual production of novel, protease-resistant protein complexes, or it may be due to the formation of protein assemblies that prevent the reverse translocation of mutant proteins to the cytosol for proteasomal proteolysis. Resistance of untransported mutant protein to ER-associated degradation will predispose to a dominant ERSD (460). In such a case, although the mutant allele could could form oligomeric hybrids with the wild-type allele, complete nonmixing of the normally exported wild-type allele and toxic accumulation of the mutant allele is another distinct scenario that can also produce a dominant mode of inheritance. (ABSTRACT TRUNCATED)