Prediction of protein-destabilizing polymorphisms by manual curation with protein structure.
The relationship between sequence polymorphisms and human disease has been studied mostly in terms of effects of single nucleotide polymorphisms (SNPs) leading to single amino acid substitutions that change protein structure and function. However, less attention has been paid to more drastic sequenc...
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2012
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oai:doaj.org-article:13bbaccc7fd44c1ebb784e2804b071a72021-11-18T08:07:33ZPrediction of protein-destabilizing polymorphisms by manual curation with protein structure.1932-620310.1371/journal.pone.0050445https://doaj.org/article/13bbaccc7fd44c1ebb784e2804b071a72012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23189203/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The relationship between sequence polymorphisms and human disease has been studied mostly in terms of effects of single nucleotide polymorphisms (SNPs) leading to single amino acid substitutions that change protein structure and function. However, less attention has been paid to more drastic sequence polymorphisms which cause premature termination of a protein's sequence or large changes, insertions, or deletions in the sequence. We have analyzed a large set (n = 512) of insertions and deletions (indels) and single nucleotide polymorphisms causing premature termination of translation in disease-related genes. Prediction of protein-destabilization effects was performed by graphical presentation of the locations of polymorphisms in the protein structure, using the Genomes TO Protein (GTOP) database, and manual annotation with a set of specific criteria. Protein-destabilization was predicted for 44.4% of the nonsense SNPs, 32.4% of the frameshifting indels, and 9.1% of the non-frameshifting indels. A prediction of nonsense-mediated decay allowed to infer which truncated proteins would actually be translated as defective proteins. These cases included the proteins linked to diseases inherited dominantly, suggesting a relation between these diseases and toxic aggregation. Our approach would be useful in identifying potentially aggregation-inducing polymorphisms that may have pathological effects.Craig Alan GoughKeiichi HommaYumi Yamaguchi-KabataMakoto K ShimadaRanajit ChakrabortyYasuyuki FujiiHisakazu IwamaShinsei MinoshimaShigetaka SakamotoYoshiharu SatoYoshiyuki SuzukiMasahito Tada-UmezakiKen NishikawaTadashi ImanishiTakashi GojoboriPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 11, p e50445 (2012) |
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Medicine R Science Q Craig Alan Gough Keiichi Homma Yumi Yamaguchi-Kabata Makoto K Shimada Ranajit Chakraborty Yasuyuki Fujii Hisakazu Iwama Shinsei Minoshima Shigetaka Sakamoto Yoshiharu Sato Yoshiyuki Suzuki Masahito Tada-Umezaki Ken Nishikawa Tadashi Imanishi Takashi Gojobori Prediction of protein-destabilizing polymorphisms by manual curation with protein structure. |
| description |
The relationship between sequence polymorphisms and human disease has been studied mostly in terms of effects of single nucleotide polymorphisms (SNPs) leading to single amino acid substitutions that change protein structure and function. However, less attention has been paid to more drastic sequence polymorphisms which cause premature termination of a protein's sequence or large changes, insertions, or deletions in the sequence. We have analyzed a large set (n = 512) of insertions and deletions (indels) and single nucleotide polymorphisms causing premature termination of translation in disease-related genes. Prediction of protein-destabilization effects was performed by graphical presentation of the locations of polymorphisms in the protein structure, using the Genomes TO Protein (GTOP) database, and manual annotation with a set of specific criteria. Protein-destabilization was predicted for 44.4% of the nonsense SNPs, 32.4% of the frameshifting indels, and 9.1% of the non-frameshifting indels. A prediction of nonsense-mediated decay allowed to infer which truncated proteins would actually be translated as defective proteins. These cases included the proteins linked to diseases inherited dominantly, suggesting a relation between these diseases and toxic aggregation. Our approach would be useful in identifying potentially aggregation-inducing polymorphisms that may have pathological effects. |
| format |
article |
| author |
Craig Alan Gough Keiichi Homma Yumi Yamaguchi-Kabata Makoto K Shimada Ranajit Chakraborty Yasuyuki Fujii Hisakazu Iwama Shinsei Minoshima Shigetaka Sakamoto Yoshiharu Sato Yoshiyuki Suzuki Masahito Tada-Umezaki Ken Nishikawa Tadashi Imanishi Takashi Gojobori |
| author_facet |
Craig Alan Gough Keiichi Homma Yumi Yamaguchi-Kabata Makoto K Shimada Ranajit Chakraborty Yasuyuki Fujii Hisakazu Iwama Shinsei Minoshima Shigetaka Sakamoto Yoshiharu Sato Yoshiyuki Suzuki Masahito Tada-Umezaki Ken Nishikawa Tadashi Imanishi Takashi Gojobori |
| author_sort |
Craig Alan Gough |
| title |
Prediction of protein-destabilizing polymorphisms by manual curation with protein structure. |
| title_short |
Prediction of protein-destabilizing polymorphisms by manual curation with protein structure. |
| title_full |
Prediction of protein-destabilizing polymorphisms by manual curation with protein structure. |
| title_fullStr |
Prediction of protein-destabilizing polymorphisms by manual curation with protein structure. |
| title_full_unstemmed |
Prediction of protein-destabilizing polymorphisms by manual curation with protein structure. |
| title_sort |
prediction of protein-destabilizing polymorphisms by manual curation with protein structure. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/13bbaccc7fd44c1ebb784e2804b071a7 |
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1718422154038476800 |