Journal
BIOINFORMATICS
Volume 24, Issue 16, Pages I241-I247Publisher
OXFORD UNIV PRESS
DOI: 10.1093/bioinformatics/btn267
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Funding
- NIGMS NIH HHS [R01 GM076643] Funding Source: Medline
- NLM NIH HHS [R01LM009722, R01 LM009722, K22LM009135, K22 LM009135] Funding Source: Medline
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Motivation: Coding-region mutations in human genes are responsible for a diverse spectrum of diseases and phenotypes. Among lesions that have been studied extensively, there are insights into several of the biochemical functions disrupted by disease-causing mutations. Currently, there are more than 60 000 coding-region mutations associated with inherited disease catalogued in the Human Gene Mutation Database (HGMD, August 2007) and more than 70 000 polymorphic amino acid substitutions recorded in dbSNP (dbSNP, build 127). Understanding the mechanism and contribution these variants make to a clinical phenotype is a formidable problem. Results: In this study, we investigate the role of phosphorylation in somatic cancer mutations and inherited diseases. Somatic cancer mutation datasets were shown to have a signi.cant enrichment for mutations that cause gain or loss of phosphorylation when compared to our control datasets (putatively neutral nsSNPs and random amino acid substitutions). Of the somatic cancer mutations, those in kinase genes represent the most enriched set of mutations that disrupt phosphorylation sites, suggesting phosphorylation target site mutation is an active cause of phosphorylation deregulation. Overall, this evidence suggests both gain and loss of a phosphorylation site in a target protein may be important features for predicting cancercausing mutations and may represent a molecular cause of disease for a number of inherited and somatic mutations.
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