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original article

A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome
Marjorie J. Lindhurst, Ph.D., Julie C. Sapp, Sc.M., Jamie K. Teer, Ph.D., Jennifer J. Johnston, Ph.D., Erin M. Finn, B.A., Kathryn Peters, M.S., Joyce Turner, M.S., Jennifer L. Cannons, Ph.D., David Bick, M.D., Laurel Blakemore, M.D.,Catherine Blumhorst, M.S.N., Knut Brockmann, M.D., Peter Calder, M.B., B.S., Natasha Cherman, Ph.D., Matthew A. Deardorff, M.D., Ph.D., David B. Everman, M.D., Gretchen Golas, M.S., Robert M. Greenstein, M.D., B. Maya Kato, M.D., Kim M. Keppler-Noreuil, M.D., Sergei A. Kuznetsov, Ph.D., Richard T. Miyamoto, M.D., Kurt Newman, M.D., David Ng, M.D., Kevin O’Brien, M.S., Steven Rothenberg, M.D., DouglasJ. Schwartzentruber, M.D., Virender Singhal, M.D., M.B.A., Roberto Tirabosco, M.D., Joseph Upton, M.D., Shlomo Wientroub, M.D., Elaine H. Zackai, M.D., Kimberly Hoag, Tracey Whitewood-Neal, Pamela G. Robey, Ph.D., Pamela L. Schwartzberg, M.D., Ph.D., Thomas N. Darling, M.D., Ph.D., Laura L. Tosi, M.D., James C. Mullikin, Ph.D., and Leslie G. Biesecker, M.D.

A bs t r ac t
Background

TheProteus 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 thoseof 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 phosphorylationspecific antibodies on Western blots.
Results

The authors’ affiliations are listedin the Appendix. Address reprint requests to Dr. Biesecker at the Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bldg. 49, Rm. 4A56, Bethesda, MD 20892, or at leslieb@helix.nih.gov. This article (10.1056/NEJMoa1104017) was published on July 27, 2011, at NEJM.org. N Engl J Med 2011;365:611-9.
Copyright © 2011 Massachusetts Medical Society.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 showedgreater 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 thePI3K–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.)
n engl j med 365;7 nejm.org august 18, 2011

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The New England Journal of Medicine Downloaded from nejm.org on November 8, 2011. For personal use only. No other uses withoutpermission. Copyright © 2011 Massachusetts Medical Society. All rights reserved.

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

he Proteus syndrome is characterized by patchy or segmental overgrowth and hyperplasia of multiple tissues and organs, along with susceptibility to the development of tumors1,2 (Fig. 1). It is thought that Joseph Merrick, an Englishman who lived in the late...
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