The distinction between cargo proteins and trafficking-machinery components can also be useful for the analysis of the mechanisms by which defective transport-related genes can lead to clinical manifestations. When a cargo protein is mutated, the pathogenetic chain of events that is set in motion can involve either a loss of function of the mutated cargo protein, because of truncation or early degradation (e.g., a channel protein, cystic fibrosis transmembrane conductance regulator) or a gain of function because of the accumulation of the mutated cargo protein in a given compartment, which would usually be the endoplasmic reticulum. This accumulation can activate the unfolded protein response. If the load of misfolded cargo exceeds the capacity of the compensatory mechanisms activated through the unfolded-protein response, the response becomes maladaptive and triggers cell damage and death. This happens, for instance, in various disorders of myelinating cells, in which mutations in genes encoding the abundant peripheral myelin protein zero are responsible for a dominant form of Charcot–Marie–Tooth disease, called CMT1B, caused by the accumulation of the protein in the endoplasmic reticulum, activation of the unfolded-protein response, and toxicity in Schwann cells.
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For mutations in the machinery proteins, a central question is how defects in conserved ubiquitous housekeeping components can give rise to manifestations that are often specific to an organ or a tissue. In a few instances, the answer is that the defective genes are predominantly expressed as specific isoforms in the affected tissues (as is the case in muscle dystrophies linked to defects in caveolin 3, the muscle-specific isoform of caveolin). In many other cases, however, the reason for this selective tissue vulnerability appears to lie in the high demand for the defective genes in the tissues that then become damaged. There appear to be two general explanations for this tissue specificity. The first is the presence of special tissue-specific cargoes, which might require high levels and full function of a particular trafficking component to be correctly transported. This occurs, for instance, in cells such as osteocytes or chondrocytes and intestinal cells, which secrete oversized cargoes. These cargoes include procollagen type I or II (rigid protofibrils measuring 300 nm in length) for osteocytes or chondrocytes and chylomicrons (particles measuring up to 1 μm in diameter) for intestinal cells. Here, mutations in the ubiquitous COPII component Sec23a or in the transport protein particle (TRAPP) complex subunit TRAPPC2 (which is involved in trafficking between the endoplasmic reticulum and the Golgi complex) can selectively affect osteocytes and chondrocytes, resulting in cranio-lenticulo-sutural dysplasia38 and spondyloepiphyseal dysplasia tarda, respectively. Along the same lines, mutations in the Sar1B GTPase that controls the COPII cycle can affect the secretion of chylomicrons in enterocytes and cause Anderson’s disease (also called chylomicron retention disease). Presumably, the same molecular defects can be compensated for in other cells and tissues by redundant mechanisms that can handle regular, but not special, cargo types.