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

Abstract

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 ...

Functional Characterization of Pendrin in a Polarized Cell System

“…8). Thus, as previously shown for other pendrin mutations (10,11), both mutations result in altered protein trafficking and at least some of the pendrin mutations appear to result in an endoplasmic reticulum storage disorder (47). As in other forms of endoplasmic reticulum storage disorders, a subset of the mutants retained in intracellular compartments may retain biological …”

“…In comparison to wild type pendrin, which shows a staining pattern consistent with membrane insertion, the expression pattern of both mutants (L676Q; FS306Ͼ309) was distinct and suggestive of retention in intracellular compartments. activity, although their processing is altered (Type A), whereas others have no functional activity (Type B) (47). Among the particularly prevalent missense mutations of pendrin, some may fall into the Type A category and become amenable to therapeutic strategies that modify the quality control in the endoplasmic reticulum, thus allowing potentially functional molecules to reach the plasma membrane.…”

Mutant PrP Is Delayed in Its Exit from the Endoplasmic Reticulum, but Neither Wild-type nor Mutant PrP Undergoes Retrotranslocation Prior to Proteasomal Degradation

“…The Role of ER Accumulation in Disease Pathogenesis-A number of inherited human diseases are attributable to defects in export of a mutant protein from the ER (22,36,49,50). In some cases, such as cystic fibrosis and hereditary hemochromatosis, the mutant protein is retrotranslocated from the ER and degraded by the proteasome, resulting in failure of the protein to reach its normal cellular destination.…”

Rescue of Calcium-sensing Receptor Mutants by Allosteric Modulators Reveals a Conformational Checkpoint in Receptor Biogenesis

“…In this report, we characterize a potential conformational or functional checkpoint affecting CaR stability during biogenesis: gain-of-function mutations or the allosteric agonist NPS R-568 stabilize CaR and increase CaR abundance, whereas loss-of-function mutations or the allosteric antagonist NPS 2143 destabilize CaR and increase degradation by ERAD. Treatment of loss-of-function mutants with NPS R-568 increases processing of the 130-kDa form to the mature 150-kDa form, resulting in increased plasma membrane localization and robust signaling in response to 5 mM Ca 2ϩ , suggesting that some CaR mutations cause a protein folding/processing defect (17,18) that can be ameliorated by pharmacochaperones (18). These results suggest that long-term treatment with calcimimetics and calcilytics can regulate turnover of CaR, providing unique possibilities for interventions in Ca 2ϩ handling diseases.…”