Three-dimensional structural location and molecular functional effects of missense SNPs in the T cell receptor Vbeta domain

The mechanisms by which human single nucleotide polymorphisms (SNPs) influence susceptibility to disease are not yet well understood. In a previous study, we developed a structure-based model that may be used to identify which missense SNPs are neutral and which are deleterious to protein function a...

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Vydané v:Proteins, structure, function, and bioinformatics Ročník 53; číslo 3; s. 748
Hlavní autori: Wang, Zhen, Moult, John
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 15.11.2003
Predmet:
Binding Sites
Genes, Immunoglobulin
Genetic Predisposition to Disease
Immunoglobulin Variable Region - chemistry
Immunoglobulin Variable Region - genetics
Models, Molecular
Mutation, Missense
Polymorphism, Single Nucleotide
Protein Binding
Protein Structure, Tertiary
Receptors, Antigen, T-Cell, alpha-beta - chemistry
Receptors, Antigen, T-Cell, alpha-beta - genetics
Receptors, Antigen, T-Cell, alpha-beta - metabolism
ISSN:1097-0134, 1097-0134
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Shrnutí:The mechanisms by which human single nucleotide polymorphisms (SNPs) influence susceptibility to disease are not yet well understood. In a previous study, we developed a structure-based model that may be used to identify which missense SNPs are neutral and which are deleterious to protein function and so potentially involved in disease (Wang and Moult, Hum Mutat 2001;263-270). The model has now been applied to a set of 54 missense cSNPs in the 46 functional T-cell receptor Vbeta-genes. Most of these missense cSNPs are found to be neutral, but 10 are identified as likely deleterious to protein function. Only one was previously associated with disease. We suggest that the others may be disease related but that redundancy in the T-cell response prevents any simple, monogenic effect. Therefore, these SNPs are the most likely contributors to complex, polygenic disease traits. It has been noted that there is a surprisingly high (74%) fraction of nonsynonymous SNPs in these genes. Contrary to expectation, the analysis shows that these are not associated with an unusually high fraction of deleterious SNPs, nor do they significantly contribute to a larger range of antigen recognition or a reduced superantigen-binding repertoire.
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ISSN:1097-0134
1097-0134
DOI:10.1002/prot.10522