Molecular mechanisms of disease-causing missense mutations

Shannon Stefl, Hafumi Nishi, Marharyta Petukh, Anna R. Panchenko, Emil Alexov

Research output: Contribution to journalReview articlepeer-review

173 Citations (Scopus)


Genetic variations resulting in a change of amino acid sequence can have a dramatic effect on stability, hydrogen bond network, conformational dynamics, activity and many other physiologically important properties of proteins. The substitutions of only one residue in a protein sequence, so-called missense mutations, can be related to many pathological conditions and may influence susceptibility to disease and drug treatment. The plausible effects of missense mutations range from affecting the macromolecular stability to perturbing macromolecular interactions and cellular localization. Here we review the individual cases and genome-wide studies that illustrate the association between missense mutations and diseases. In addition, we emphasize that the molecular mechanisms of effects of mutations should be revealed in order to understand the disease origin. Finally, we report the current state-of-the-art methodologies that predict the effects of mutations on protein stability, the hydrogen bond network, pH dependence, conformational dynamics and protein function.

Original languageEnglish
Pages (from-to)3919-3936
Number of pages18
JournalJournal of Molecular Biology
Issue number21
Publication statusPublished - 2013 Nov 1
Externally publishedYes


  • SNP
  • diseases
  • genetic variation
  • rare mutations
  • single nucleotide polymorphism

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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