The relationship between sequence polymorphisms and human disease has been studied mostly in terms of effects of\r\nsingle nucleotide polymorphisms (SNPs) leading to single amino acid substitutions that change protein structure and\r\nfunction. However, less attention has been paid to more drastic sequence polymorphisms which cause premature\r\ntermination of a protein�s sequence or large changes, insertions, or deletions in the sequence. We have analyzed a large set\r\n(n = 512) of insertions and deletions (indels) and single nucleotide polymorphisms causing premature termination of\r\ntranslation in disease-related genes. Prediction of protein-destabilization effects was performed by graphical presentation of\r\nthe locations of polymorphisms in the protein structure, using the Genomes TO Protein (GTOP) database, and manual\r\nannotation with a set of specific criteria. Protein-destabilization was predicted for 44.4% of the nonsense SNPs, 32.4% of the\r\nframeshifting indels, and 9.1% of the non-frameshifting indels. A prediction of nonsense-mediated decay allowed to infer\r\nwhich truncated proteins would actually be translated as defective proteins. These cases included the proteins linked to\r\ndiseases inherited dominantly, suggesting a relation between these diseases and toxic aggregation. Our approach would be\r\nuseful in identifying potentially aggregation-inducing polymorphisms that may have pathological effects.
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