Protein destabilization and the Diseasome

Human genetic variation is mainly due to Single Nucleotide Polymorphisms (SNPs), accounting for about 90% of overall variations (Collins et al., 1998). One of the main interests of Bioinformatics in relation to SNPs is the understanding of mechanisms responsible for the insurgence of pathologic phenomena related to genetic mutations (Risch et al 1996, Collins et al., 1997). In general, mutations occurring in coding regions may have a greater dramatic impact on the gene functionality (Cargill et al 1999) and for this reason we focus our attention on those SNPs, called missense SNPs (mSNPs) that cause changes in the protein sequence. Mutations can impair proteins when the mutation is directed towards functional residues, and more generally acting on protein stability and/or affecting protein-protein interactions patches. In a recent work, in order to simplify the problem of disease ontology, a network of disorders and disease linked genes [about 2000] was generated on the basis of known disorder–gene associations (the human Diseasome, Goh et al. 2007). The network indicates that the vast majority of disease related genes are nonessential and show no tendency to encode for hub proteins in the human interactome. When mutations occur in essential genes, these are mainly responsible of cancer insurgence (Goh et al. 2007). A major problem in disease related mutations is also at which extent the mutation is affecting protein stability. The protein stability issue relating to human disease is well established for proteins involved in the phenomena of protein aggregation leading to the formation of amyloid fibers in maladies of dramatic social impact such as Alzheimer, Parkinson and Creutzfeldt-Jakob diseases (Chiti and Dobson, 2006). It is therefore relevant to ask the question as to whether and to which extent mutations, diseases and protein misfolding are related starting from the data of polymorphisms that are presently available. In this paper we will focus on how to predict protein destabilazion and accordingly we will discuss some extent of correlation among protein destabilization and specific mutations, suggesting that protein destabilization is a major feature common to several diseases in the Diseasome.