A mosaic activating mutation in AKT1 associated with the Proteus syndrome.


BACKGROUND The Proteus syndrome is characterized by the overgrowth of skin, connective tissue, brain, and other tissues. It has been hypothesized that the syndrome is caused by somatic mosaicism for a mutation that is lethal in the nonmosaic state. METHODS We performed exome sequencing of DNA from biopsy samples obtained from patients with the Proteus syndrome and compared the resultant DNA sequences with those of unaffected tissues obtained from the same patients. We confirmed and extended an observed association, using a custom restriction-enzyme assay to analyze the DNA in 158 samples from 29 patients with the Proteus syndrome. We then assayed activation of the AKT protein in affected tissues, using phosphorylation-specific antibodies on Western blots. RESULTS Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1, encoding the AKT1 kinase, an enzyme known to mediate processes such as cell proliferation and apoptosis. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines. A pair of single-cell clones that were established from the same starting culture and differed with respect to their mutation status had different levels of AKT phosphorylation. CONCLUSIONS The Proteus syndrome is caused by a somatic activating mutation in AKT1, proving the hypothesis of somatic mosaicism and implicating activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. (Funded by the Intramural Research Program of the National Human Genome Research Institute.).

DOI: 10.1056/NEJMoa1104017
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@article{Lindhurst2011AMA, title={A mosaic activating mutation in AKT1 associated with the Proteus syndrome.}, author={Marjorie J. Lindhurst and Julie Chevalier Sapp and Jamie K. Teer and Jennifer J Johnston and Erin M Finn and Kathryn F. Peters and Joyce T Turner and Jennifer L. Cannons and David Bick and Laurel C Blakemore and Catherine Blumhorst and Knut Brockmann and Peter R Calder and Natasha Cherman and Matthew A Deardorff and David B. Everman and Gretchen A. Golas and Robert M Greenstein and Bunichiro Kato and Kim M Keppler-Noreuil and Sergei A. Kuznetsov and Richard T. Miyamoto and Kurt D . Newman and David Ng and Kevin E O'Brien and Steven S. Rothenberg and Douglas J. Schwartzentruber and Virender Singhal and Roberto Tirabosco and Joseph Upton and Shlomo Wientroub and Elaine H. Zackai and Kimberly Hoag and Tracey Whitewood-Neal and Pamela Robey and Pamela L Schwartzberg and Thomas N Darling and Laura Lowe Tosi and James C. Mullikin and Leslie G. Biesecker}, journal={The New England journal of medicine}, year={2011}, volume={365 7}, pages={611-9} }