Title

A mosaic activating mutation in AKT1 associated with the proteus syndrome

Authors

Marjorie J. Lindhurst, Uniformed Services University of the Health Sciences
Julie C. Sapp, Uniformed Services University of the Health Sciences
Jamie K. Teer, Uniformed Services University of the Health Sciences
Jennifer J. Johnston, Uniformed Services University of the Health Sciences
Erin M. Finn, Uniformed Services University of the Health Sciences
Kathryn Peters, Uniformed Services University of the Health Sciences
Joyce Turner, Uniformed Services University of the Health Sciences
Jennifer L. Cannons, Uniformed Services University of the Health Sciences
David Bick, Medical College of Wisconsin
Laurel Blakemore, Childrens National Health System
Catherine Blumhorst, Uniformed Services University of the Health Sciences
Knut Brockmann, Universität Göttingen
Peter Calder, Royal National Orthopaedic Hospital NHS Trust
Natasha Cherman, Uniformed Services University of the Health Sciences
Matthew A. Deardorff, The Children's Hospital of Philadelphia
David B. Everman, Greenwood Genetics Center
Gretchen Golas, Uniformed Services University of the Health Sciences
Robert M. Greenstein, University of Connecticut Hartford Campus
B. Maya Kato, Ear Research Institute
Kim M. Keppler-Noreuil, University of Iowa
Sergei A. Kuznetsov, Uniformed Services University of the Health Sciences
Richard T. Miyamoto, Indiana University-Purdue University Indianapolis
Kurt Newman, Childrens National Health System
David Ng, Uniformed Services University of the Health Sciences
Kevin O'Brien, Uniformed Services University of the Health Sciences
Steven Rothenberg, Rocky Mountain Hospital for Children
Douglas J. Schwartzentruber, Uniformed Services University of the Health Sciences
Virender Singhal, Children's Mercy Hospitals and Clinics
Roberto Tirabosco, Royal National Orthopaedic Hospital NHS Trust
Joseph Upton, Children's Hospital Boston
Shlomo Wientroub, Tel Aviv University
Elaine H. Zackai, The Children's Hospital of Philadelphia
Kimberly Hoag, Proteus Syndrome Foundation

Document Type

Journal Article

Publication Date

8-18-2011

Journal

New England Journal of Medicine

Volume

365

Issue

7

DOI

10.1056/NEJMoa1104017

Abstract

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.) Copyright © 2011 Massachusetts Medical Society.

This document is currently not available here.

Share

COinS