TY - JOUR
T1 - Molecular mechanisms of disease-causing missense mutations
AU - Stefl, Shannon
AU - Nishi, Hafumi
AU - Petukh, Marharyta
AU - Panchenko, Anna R.
AU - Alexov, Emil
N1 - Funding Information:
S.S., M.P, and E.A. acknowledge the support from the National Institutes of Health grant number R01GM093937. H.N. and A.R.P. were supported by the Intramural Research Program of the National Library of Medicine at the US National Institutes of Health.
PY - 2013/11/1
Y1 - 2013/11/1
N2 - 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.
AB - 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.
KW - SNP
KW - diseases
KW - genetic variation
KW - rare mutations
KW - single nucleotide polymorphism
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U2 - 10.1016/j.jmb.2013.07.014
DO - 10.1016/j.jmb.2013.07.014
M3 - Review article
C2 - 23871686
AN - SCOPUS:84885184466
VL - 425
SP - 3919
EP - 3936
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 21
ER -