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From Bioinformatics to Bioassays: Gleaning Insights into Protein Structure-Function from Disease-Associated nsSNPs

Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute–Frederick, National Institutes of Health, Frederick, MD 21702-1201

SUMMARY

Non-synonymous single nucleotide polymorphisms (SNPs) that result in amino acid sub-stitutions may have no appreciable effect on protein function, but those that involve critical residues may cause or contribute to disease. Large-scale gene sequencing studies have revealed a daunting number of non-synonymous SNPs with unknown functional consequences. Both predictive techniques and functional assays can aid in the identification of disease-relevant SNPs, as illustrated by two recent reports. An insightful comparison of known disease-causing vs uncharacterized SNPs in protein kinases sheds new light on regions of the catalytic core. The observed prevelance of disease-causing SNPs in substrate binding and regulatory regions––but paucity thereof in residues directly involved in the catalytic reaction––will likely extend to other enzymes as well. A clever functional bioassay using mouse ES cells distinguishes neutral from deleterious mutations in the breast and ovarian cancer-related BRCA2 gene, which may aid in the interpretation of patient BRCA2 screening data.