エレファントマンのことを正式にはProteus Syndromeという・・という記事を最近読んだところだったので私的にはタイムリーなニュースである。この病気の責任遺伝子がAKT1 の突然変異であること。この病気はモザイクであることなどがNEJMに報告されている。（今ならpdfはフリーでdownloadできる）
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., Douglas J. 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.
July 27, 2011 (10.1056/NEJMoa1104017)
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.
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.
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.
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.)