Variation in Akt protein kinases in human populations.

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The three Akt kinases are related proteins that are essential for normal growth and metabolic regulation and are implicated as key signaling mediators in many physiological and pathophysiological processes. Each Akt is activated by common biochemical signals that act downstream of growth factor and hormone receptors via phosphatidylinositol-3 kinase, and each controls several downstream pathways. The importance of Akt actions in human physiology is strengthened by the rarity of modifying mutations in their genes and by the devastating impact caused by these mutations on growth and development and in disorders such as cancer. Recent advances in genomics present unique opportunities for enhancing our understanding of human physiology and disease predisposition through the lens of population genetics, and the availability of DNA sequence data from 60,706 people in the Exome Aggregation Consortium has prompted this analysis. Results reveal a cohort of potential missense and other alterations in the coding regions of each AKT gene, but with nearly all changes being uncommon. The total number of different alleles per gene varied over an approximately threefold range, from 52 for AKT3 to 158 for AKT2, with variants distributed throughout all Akt protein domains. Previously characterized disease-causing mutations were found rarely in the general population. In contrast, a fairly prevalent amino acid substitution in AKT2 appears to be linked to increased predisposition for type 2 diabetes. Further analysis of variant Akt molecules as identified here will provide opportunities to understand the intricacies of Akt signaling and actions at a population level in human physiology and pathology.