Pathogenic or not? And if so, then how? Studying the effects of missense mutations using bioinformatics methods

Hum Mutat. 2009 May;30(5):703-14. doi: 10.1002/humu.20938.


Many gene defects are relatively easy to identify experimentally, but obtaining information about the effects of sequence variations and elucidation of the detailed molecular mechanisms of genetic diseases will be among the next major efforts in mutation research. Amino acid substitutions may have diverse effects on protein structure and function; thus, a detailed analysis of the mutations is essential. Experimental study of the molecular effects of mutations is laborious, whereas useful and reliable information about the effects of amino acid substitutions can readily be obtained by theoretical methods. Experimentally defined structures and molecular modeling can be used as a basis for interpretation of the mutations. The effects of missense mutations can be analyzed even when the 3D structure of the protein has not been determined, although structure-based analyses are more reliable. Structural analyses include studies of the contacts between residues, their implication for the stability of the protein, and the effects of the introduced residues. Investigations of steric and stereochemical consequences of substitutions provide insights on the molecular fit of the introduced residue. Mutations that change the electrostatic surface potential of a protein have wide-ranging effects. Analyses of the effects of mutations on interactions with ligands and partners have been performed for elucidation of functional mutations. We have employed numerous methods for predicting the effects of amino acid substitutions. We discuss the applicability of these methods in the analysis of genes, proteins, and diseases to reveal protein structure-function relationships, which is essential to gain insights into disease genotype-phenotype correlations.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Computational Biology / methods*
  • Humans
  • Mutation, Missense / genetics*
  • Protein Structure, Secondary