A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome

作者：Marjorie J. Lindhurst, Julie C. Sapp, Jamie K. Teer, Jennifer J. Johnston, Erin Finn, Kathryn F. Peters, Joyce Tannenbaum Turner, Jennifer Leigh Cannons, David P Bick, Laurel C. Blakemore, Catherine Blumhorst, Knut Brockmann, Peter Calder, Natasha Cherman, Matthew A. Deardorff, David B. Everman, Gretchen A. Golas, Robert M. Greenstein, B. Maya Kato, Kim M. Keppler‐Noreuil, Sergei A. Kuznetsov, Richard T. Miyamoto, Kurt D. Newman, David Chi-Heng Ng, Kevin D O'Brien, Steven Rothenberg, Douglas J. Schwartzentruber, Virender K. Singhal, Roberto Tirabosco, Joseph M. Upton, Shlomo Wientroub, Elaine H. Zackai, Kimberly Hoag, Tracey Whitewood-Neal, Pamela Gehron Robey, Pamela L. Schwartzberg, Thomas N. Darling, Laura Lowe Tosi, James C. Mullikin, Leslie G. Biesecker · 发表于：New England Journal of Medicine · 年份：2011 · DOI：10.1056/nejmoa1104017 · 被引用次数：917 · 研究领域：Vascular Malformations and Hemangiomas、Soft tissue tumors and treatment、Dupuytren's Contracture and Treatments

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, provin...