In silico modeling of the effects of missense mutations causing mental disorders

Emil Alexov (April 26, 2011)

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Human DNA sequence differs among individuals and the most common variations are known as single nucleotide polymorphisms, or SNPs. Studies have shown that non-synonymous coding SNPs (nsSNPs - SNPs occurring in protein coding regions which lead to amino acid substitutions) can be responsible for many human diseases or cause the natural differences among the individuals by affecting the structure, function, interactions and other properties of expressed proteins. Of particular interest for us are rare missense mutations causing mental disorders by affecting the wild type characteristics of a certain protein. In this talk we will focus on three cases, spermine synthase, CLIC2 and SLC8A6 proteins, missense mutations in which were clinically shown to cause mental disorders. We demonstrate that in vast majority of the cases the mutations do not directly affect the functional properties of the corresponding protein, but rather indirectly alter its wild type characteristics. Further we contrast the effects caused by disease-causing missense mutations and naturally occurring harmless nsSNPs. It is demonstrated that disease-causing mutations do not necessary destabilize protein stability or protein-protein interactions, but can be stabilizing and still be harmful. Overall, a detailed computational analysis combined with an analysis of the corresponding biological function is needed to make reasonable prediction of the nature of the missense mutation.