Investigations of genetic diseases such as cystic fibrosis, alpha-1-antitrypsin deficiency, phenylketonuria, mitochondrial acyl-CoA dehydrogenase deficiencies, and many others have shown that enhanced proteolytic degradation of mutant proteins is a common molecular pathological mechanism. Detailed studies of the fate of mutant proteins in some of these diseases have revealed that impaired or aberrant folding of mutant polypeptides typically results in prolonged interaction with molecular chaperones and degradation by intracellular proteases before the functional conformation is acquired. This appears to be the case for many missense mutations and short in-frame deletions or insertions that represent a major fraction of the mutations detected in genetic diseases. In some diseases, or under some circumstances, the degradation system is not efficient. Instead, aberrant folding leads to accumulation of protein aggregates that damage the cell. Mechanisms by which misfolded proteins are selected for degradation have first been delineated for the endoplasmatic reticulum; this process has been termed "protein quality control." Similar mechanisms appear to be operative in all cellular compartments in which proteins fold. Within the context of genetic diseases, we review knowledge on the molecular processes underlying protein quality control in the various subcellular compartments. The important impact of such systems for variability of the expression of genetic deficiencies is emphasised.
Copyright 1999 Wiley-Liss, Inc.