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  • Missense gene variations constitute about half of all disease-causing sequence variations as well as a large number of susceptibility single nucleotide polymorphisms (SNPs) associated with inherited disorders.

  • Missense gene variations may result in misfolding of the corresponding variant proteins; a conformational disease may result. Depending on the protein itself, and on the type and location of the variation in the particular protein, the resulting disease can be classified as a "loss-of-function" or a "gain-of-function" conformational disease.

  • An important determinant 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 aggregates or forms toxic dominant negative protein species have gain-of-function pathogenesis.

  • The effect of a given missense variation may--as a first approach--be predicted from the physicochemical alterations evaluated from the crystal structure of the protein. However, since the defects in most cases affect folding, and because folding pathways are not known for any disease-related proteins, a precise prediction is not yet possible.

  • 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 in addition to chaperones involve intracellular proteases.

  • The most important chaperones are the Hsp70 family, Hsp90, and small Hsps, as well as the chaperonins (barrel-formed chaperones), of which mitochondrial Hsp60 and cytosolic TCP-1 ring complex (TRiC) are the best known. The endoplasmic reticulum (ER) also contains a number of lectin chaperones, which bind glycosylated proteins and assist in their folding. In addition to these general chaperones, a large number of specialized chaperones exist; they assist in the folding and assembly of specific protein complexes, such as respiratory chain complexes and complexes involved in the lipid metabolism. 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.

  • PQC systems are involved in the biogenesis of newly synthesized proteins and supervise the acquisition of the functional structure. A large portion of protein molecules--up to 30%--never reach the native structure, either because they carry transcriptional/translational errors or because 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 genetic defects or as a consequence of advanced age, 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 protein is eliminated due to missense sequence variations, efficiency of the PQC systems will determine the degree of functional deficiency and clinical expression (phenotype).

  • Type and location of the sequence variation, efficiency of the PQC systems, and cellular stress each contribute to molecular pathogenesis and disease expression. Cellular stress elicits a response involving induction of chaperones, which may alleviate the effect of ...

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