Prediction of Protein-Destabilizing Polymorphisms by Manual Curation with Protein Structure

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish (US)
Article numbere50445
JournalPloS one
Issue number11
StatePublished - Nov 26 2012
Externally publishedYes

ASJC Scopus subject areas

  • General


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