Degradation of Mutant Proteins, Underlying "Loss of Function" Phenotypes, Plays a Major Role in Genetic Disease

Many Mendelian monogenic disorders are caused by loss of the function of a single protein. This can result from rapid degradation of the mutant protein by cellular proteases, which reduces the steady-state concentration of the protein within the cell. The susceptibility of a protein to such proteolytic breakdown depends upon its kinetics of monomer folding and oligomer assembly and upon the intrinsic (thermodynamic) stability of its functional native-state conformation. Other cellular proteins, notably molecular chaperones, promote correct protein folding and assembly and thus provide some protection against degradation. An accumulation of recent evidence indicates that premature or accelerated degradation of mutant proteins, provoked by aberrations in their conformation, occurs in various subcellular compartments and represents a significant and prevalent pathogenic mechanism underlying genetic diseases. Inter-individual variability in proteolytic and folding systems can in part explain why "simple monogenic diseases" often display inconsistent genotype-phenotype correlations which show these disorders to be in reality quite complex. Protein folding and degradation may also be modulated artificially using exogenous small molecules. The identification or design of compounds which can interact specifically with particular target proteins, and which in so doing can exert beneficial effects on protein folding, assembly and/or stability, is beginning to open up a new and remarkably promising avenue for the treatment of diverse genetic disorders.