Endocrine Reviews: Defective Protein Folding

Beyond the Signal Sequence: Protein Routing in Health and Disease
This article focuses on the various diseases that originate from improper protein folding. The intracellular routing for many proteins is controlled by a sensitive QC, quality control, system. This system recognizes structural proteins as well as destroys defective molecules. Abnormal proteins are capable of interfering with normal cell function and can lead to cell death. Diseases that are caused by abnormal proteins usually involve the inability of a protein, or protein complex, to carry out its normal function or when a protein is incorrectly folded. Another cause is when proteins are not properly positioned within a cell.
One disease that results from improper protein folding is nephrogenic diabetes insipidus (NDI). This disease can either be inherited or acquired. The kidneys are unable to concentrate urine, even if there are normal levels of the antidiuretic hormone vasopressin present in the plasma. Vasopressin aids the body by regulating water loss and retention, by reabsoprtion of water from urine and by fusing vesicles that hold aquaporin-2 (AQP2) water channels. This prevents an increase in the water permeability within the ducts.  NDI can be caused if there are mutations in the vasopressin type 2 receptor (V2R) gene or in the AQP2 gene. The X-linked version of NDI is caused by mutations to the VR2 gene while the more rare, non-X linked version is caused by mutations to the AQP2 gene.
In VR2 mutations, more than 90% were unable to perform effective intracellular transport due to improper folding. There may also be an accumulation of VR2 in the ER. In AQP2 mutations, proteins are incapable of proper trafficking, causing the protein to remain in the ER. One type of mutation in the AQP2 has resulted in an inherited NDI that is autosomal-dominant.