title: Prediction of protein-destabilizing polymorphisms by manual curation with protein structure.
abstract: 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.
authors.affiliation: Integrated Database Group, Japan Biological Information Research Center, Tokyo, Japan.
authors.forename: Craig Alan
authors.initials: CA
authors.lastname: Gough
authors.forename: Keiichi
authors.initials: K
authors.lastname: Homma
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yamaguchi-Kabata
authors.forename: Makoto K
authors.initials: MK
authors.lastname: Shimada
authors.forename: Ranajit
authors.initials: R
authors.lastname: Chakraborty
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujii
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Iwama
authors.forename: Shinsei
authors.initials: S
authors.lastname: Minoshima
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Sato
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Masahito
authors.initials: M
authors.lastname: Tada-Umezaki
authors.forename: Ken
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Tadashi
authors.initials: T
authors.lastname: Imanishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Gojobori
mesh_terms: D030562:Databases, Protein; D020022:Genetic Predisposition to Disease; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D054643:INDEL Mutation; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*
chemical_list: D011506:Proteins