title: SNPs, protein structure, and disease.
abstract: Inherited disease susceptibility in humans is most commonly associated with single nucleotide polymorphisms (SNPs). The mechanisms by which this occurs are still poorly understood. We have analyzed the effect of a set of disease-causing missense mutations arising from SNPs, and a set of newly determined SNPs from the general population. Results of in vitro mutagenesis studies, together with the protein structural context of each mutation, are used to develop a model for assigning a mechanism of action of each mutation at the protein level. Ninety percent of the known disease-causing missense mutations examined fit this model, with the vast majority affecting protein stability, through a variety of energy related factors. In sharp contrast, over 70% of the population set are found to be neutral. The remaining 30% are potentially involved in polygenic disease.
authors: Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, Maryland 20850, USA.
authors: Z
authors: Z
authors: Wang
authors: J
authors: J
authors: Moult
mesh_terms: D000494:Allosteric Regulation; D002384:Catalysis; D019295:Computational Biology; D019992:Databases as Topic; D004220:Disulfides / Q000378:metabolism; D004795:Enzyme Stability / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D020412:Multifactorial Inheritance / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D004220:Disulfides; D008024:Ligands; D011506:Proteins