title: A mosaic activating mutation in AKT1 associated with the Proteus syndrome.
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.).
authors.affiliation: National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Marjorie J
authors.initials: MJ
authors.lastname: Lindhurst
authors.forename: Julie C
authors.initials: JC
authors.lastname: Sapp
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Johnston
authors.forename: Erin M
authors.initials: EM
authors.lastname: Finn
authors.forename: Kathryn
authors.initials: K
authors.lastname: Peters
authors.forename: Joyce
authors.initials: J
authors.lastname: Turner
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cannons
authors.forename: David
authors.initials: D
authors.lastname: Bick
authors.forename: Laurel
authors.initials: L
authors.lastname: Blakemore
authors.forename: Catherine
authors.initials: C
authors.lastname: Blumhorst
authors.forename: Knut
authors.initials: K
authors.lastname: Brockmann
authors.forename: Peter
authors.initials: P
authors.lastname: Calder
authors.forename: Natasha
authors.initials: N
authors.lastname: Cherman
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.forename: David B
authors.initials: DB
authors.lastname: Everman
authors.forename: Gretchen
authors.initials: G
authors.lastname: Golas
authors.forename: Robert M
authors.initials: RM
authors.lastname: Greenstein
authors.forename: B Maya
authors.initials: BM
authors.lastname: Kato
authors.forename: Kim M
authors.initials: KM
authors.lastname: Keppler-Noreuil
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Kuznetsov
authors.forename: Richard T
authors.initials: RT
authors.lastname: Miyamoto
authors.forename: Kurt
authors.initials: K
authors.lastname: Newman
authors.forename: David
authors.initials: D
authors.lastname: Ng
authors.forename: Kevin
authors.initials: K
authors.lastname: O'Brien
authors.forename: Steven
authors.initials: S
authors.lastname: Rothenberg
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Schwartzentruber
authors.forename: Virender
authors.initials: V
authors.lastname: Singhal
authors.forename: Roberto
authors.initials: R
authors.lastname: Tirabosco
authors.forename: Joseph
authors.initials: J
authors.lastname: Upton
authors.forename: Shlomo
authors.initials: S
authors.lastname: Wientroub
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.forename: Kimberly
authors.initials: K
authors.lastname: Hoag
authors.forename: Tracey
authors.initials: T
authors.lastname: Whitewood-Neal
authors.forename: Pamela G
authors.initials: PG
authors.lastname: Robey
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Darling
authors.forename: Laura L
authors.initials: LL
authors.lastname: Tosi
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
mesh_terms: D002648:Child; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D009030:Mosaicism; D009154:Mutation; D010766:Phosphorylation; D016715:Proteus Syndrome / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism
chemical_list: D051057:Proto-Oncogene Proteins c-akt