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ABSTRACT

  1. More than half of all disease-causing sequence variations associated with inherited disorders as well as a significant fraction of single nucleotide polymorphisms (SNPs) that may confer susceptibility to disease conditions are missense variants.

  2. Missense variants may result in misfolding of the corresponding variant proteins, and a protein conformational disease may develop. Dependent on the protein as well as the type and location of the variation in the particular protein, the resulting disease can be categorized as mainly a loss-of-function or a gain-of-function conformational disease.

  3. An important determinant for the type of conformational disease is the ability of the protein quality control (PQC) systems of the cell to eliminate the misfolded proteins in question. Disorders involving proteins that are rapidly eliminated develop mainly loss-of-function pathologies. Diseases in which the misfolded protein escapes the PQC systems and forms aggregates or toxic dominant negative protein species often develop gain-of-function pathologies as the main determinant. All misfolded proteins constitute a burden on the cell and may evoke stress responses.

  4. The effect of a given missense variation may—as a first approach—be predicted from the degree of evolutionary conservation and physicochemical alterations evaluated from the native structure of the protein. However, since disease-causing missense variations in a majority of cases affect folding to the native state, and because for most proteins folding of variant proteins cannot yet be appropriately modeled, a trustworthy prediction based solely on the position and type of replacement is problematic.

  5. The acquisition of the functional structure through the folding pathway of wild-type as well as missense variant proteins is assisted by chaperones and supervised by organelle-specific PQC systems, which consist of chaperones, particular proteases, and regulatory factors.

  6. The most important chaperones are members of the Hsp70 family, the Hsp90s, the small HSPs, and the chaperonins. The endoplasmic reticulum also contains a number of lectin chaperones that bind glycosylated proteins and assist their folding. In addition to these general chaperones a large number of specialized chaperones exist that assist in the folding and assembly of specific protein complexes, such as respiratory chain complexes. The proteases of the PQC systems constitute a large variety of organelle-specific complexes, of which the proteasome and the AAA+-domain proteases are the most important.

  7. The PQC systems are involved in the biogenesis of newly synthesized proteins by supervising the acquisition of the functional structure. A large number of newly synthesized protein molecules—up to 30%—never reach the native structure, because either they carry transcriptional/translational errors or they carry missense sequence variations. Efficient PQC systems are thus necessary for the proper function of the cell. If the systems are not efficient, either because of the extra load added by genetic defects or as a consequence of age-dependent decline, misfolded proteins accumulate and may give rise to aggregation/gain-of-function diseases. On the other hand, in loss-of-function disorders where the misfolded variant protein is eliminated, the efficiency of the PQC systems will be determining for the degree of functional deficiency and thereby for the ...

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