A mosaic activating mutation in AKT1 associated with the proteus syndrome

Marjorie J. Lindhurst, Julie C. Sapp, Jamie K. Teer, Jennifer J. Johnston, Erin M. Finn, Kathryn Peters, Joyce Turner, Jennifer L. Cannons, David Bick, Laurel Blakemore, Catherine Blumhorst, Knut Brockmann, Peter Calder, Natasha Cherman, Matthew A. Deardorff, David B. Everman, Gretchen Golas, Robert M. Greenstein, B. Maya Kato, Kim M. Keppler-NoreuilSergei A. Kuznetsov, Richard Miyamoto, Kurt Newman, David Ng, Kevin O'Brien, Steven Rothenberg, Douglas J. Schwartzentruber, Virender Singhal, Roberto Tirabosco, Joseph Upton, Shlomo Wientroub, Elaine H. Zackai, Kimberly Hoag, Tracey Whitewood-Neal, Pamela G. Robey, Pamela L. Schwartzberg, Thomas N. Darling, Laura L. Tosi, James C. Mullikin, Leslie G. Biesecker

Research output: Contribution to journalArticle

472 Citations (Scopus)

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.)

Original languageEnglish
Pages (from-to)611-619
Number of pages9
JournalNew England Journal of Medicine
Volume365
Issue number7
DOIs
StatePublished - Aug 18 2011

Fingerprint

Proteus Syndrome
Mutation
Mosaicism
Phosphorylation
Cell Line
National Human Genome Research Institute (U.S.)
Exome
Enzyme Assays
Phosphatidylinositol 3-Kinases
DNA Sequence Analysis
Oncogenes
Connective Tissue
Phosphotransferases
Clone Cells
Western Blotting
Alleles
Cell Proliferation
Apoptosis
Biopsy
Skin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lindhurst, M. J., Sapp, J. C., Teer, J. K., Johnston, J. J., Finn, E. M., Peters, K., ... Biesecker, L. G. (2011). A mosaic activating mutation in AKT1 associated with the proteus syndrome. New England Journal of Medicine, 365(7), 611-619. https://doi.org/10.1056/NEJMoa1104017

A mosaic activating mutation in AKT1 associated with the proteus syndrome. / Lindhurst, Marjorie J.; Sapp, Julie C.; Teer, Jamie K.; Johnston, Jennifer J.; Finn, Erin M.; Peters, Kathryn; Turner, Joyce; Cannons, Jennifer L.; Bick, David; Blakemore, Laurel; Blumhorst, Catherine; Brockmann, Knut; Calder, Peter; Cherman, Natasha; Deardorff, Matthew A.; Everman, David B.; Golas, Gretchen; Greenstein, Robert M.; Kato, B. Maya; Keppler-Noreuil, Kim M.; Kuznetsov, Sergei A.; Miyamoto, Richard; Newman, Kurt; Ng, David; O'Brien, Kevin; Rothenberg, Steven; Schwartzentruber, Douglas J.; Singhal, Virender; Tirabosco, Roberto; Upton, Joseph; Wientroub, Shlomo; Zackai, Elaine H.; Hoag, Kimberly; Whitewood-Neal, Tracey; Robey, Pamela G.; Schwartzberg, Pamela L.; Darling, Thomas N.; Tosi, Laura L.; Mullikin, James C.; Biesecker, Leslie G.

In: New England Journal of Medicine, Vol. 365, No. 7, 18.08.2011, p. 611-619.

Research output: Contribution to journalArticle

Lindhurst, MJ, Sapp, JC, Teer, JK, Johnston, JJ, Finn, EM, Peters, K, Turner, J, Cannons, JL, Bick, D, Blakemore, L, Blumhorst, C, Brockmann, K, Calder, P, Cherman, N, Deardorff, MA, Everman, DB, Golas, G, Greenstein, RM, Kato, BM, Keppler-Noreuil, KM, Kuznetsov, SA, Miyamoto, R, Newman, K, Ng, D, O'Brien, K, Rothenberg, S, Schwartzentruber, DJ, Singhal, V, Tirabosco, R, Upton, J, Wientroub, S, Zackai, EH, Hoag, K, Whitewood-Neal, T, Robey, PG, Schwartzberg, PL, Darling, TN, Tosi, LL, Mullikin, JC & Biesecker, LG 2011, 'A mosaic activating mutation in AKT1 associated with the proteus syndrome', New England Journal of Medicine, vol. 365, no. 7, pp. 611-619. https://doi.org/10.1056/NEJMoa1104017
Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K et al. A mosaic activating mutation in AKT1 associated with the proteus syndrome. New England Journal of Medicine. 2011 Aug 18;365(7):611-619. https://doi.org/10.1056/NEJMoa1104017
Lindhurst, Marjorie J. ; Sapp, Julie C. ; Teer, Jamie K. ; Johnston, Jennifer J. ; Finn, Erin M. ; Peters, Kathryn ; Turner, Joyce ; Cannons, Jennifer L. ; Bick, David ; Blakemore, Laurel ; Blumhorst, Catherine ; Brockmann, Knut ; Calder, Peter ; Cherman, Natasha ; Deardorff, Matthew A. ; Everman, David B. ; Golas, Gretchen ; Greenstein, Robert M. ; Kato, B. Maya ; Keppler-Noreuil, Kim M. ; Kuznetsov, Sergei A. ; Miyamoto, Richard ; Newman, Kurt ; Ng, David ; O'Brien, Kevin ; Rothenberg, Steven ; Schwartzentruber, Douglas J. ; Singhal, Virender ; Tirabosco, Roberto ; Upton, Joseph ; Wientroub, Shlomo ; Zackai, Elaine H. ; Hoag, Kimberly ; Whitewood-Neal, Tracey ; Robey, Pamela G. ; Schwartzberg, Pamela L. ; Darling, Thomas N. ; Tosi, Laura L. ; Mullikin, James C. ; Biesecker, Leslie G. / A mosaic activating mutation in AKT1 associated with the proteus syndrome. In: New England Journal of Medicine. 2011 ; Vol. 365, No. 7. pp. 611-619.
@article{97eb0b03a74545bba180a2f9dab09401,
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.)",
author = "Lindhurst, {Marjorie J.} and Sapp, {Julie C.} and Teer, {Jamie K.} and Johnston, {Jennifer J.} and Finn, {Erin M.} and Kathryn Peters and Joyce Turner and Cannons, {Jennifer L.} and David Bick and Laurel Blakemore and Catherine Blumhorst and Knut Brockmann and Peter Calder and Natasha Cherman and Deardorff, {Matthew A.} and Everman, {David B.} and Gretchen Golas and Greenstein, {Robert M.} and Kato, {B. Maya} and Keppler-Noreuil, {Kim M.} and Kuznetsov, {Sergei A.} and Richard Miyamoto and Kurt Newman and David Ng and Kevin O'Brien and Steven Rothenberg and Schwartzentruber, {Douglas J.} and Virender Singhal and Roberto Tirabosco and Joseph Upton and Shlomo Wientroub and Zackai, {Elaine H.} and Kimberly Hoag and Tracey Whitewood-Neal and Robey, {Pamela G.} and Schwartzberg, {Pamela L.} and Darling, {Thomas N.} and Tosi, {Laura L.} and Mullikin, {James C.} and Biesecker, {Leslie G.}",
year = "2011",
month = "8",
day = "18",
doi = "10.1056/NEJMoa1104017",
language = "English",
volume = "365",
pages = "611--619",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "7",

}

TY - JOUR

T1 - A mosaic activating mutation in AKT1 associated with the proteus syndrome

AU - Lindhurst, Marjorie J.

AU - Sapp, Julie C.

AU - Teer, Jamie K.

AU - Johnston, Jennifer J.

AU - Finn, Erin M.

AU - Peters, Kathryn

AU - Turner, Joyce

AU - Cannons, Jennifer L.

AU - Bick, David

AU - Blakemore, Laurel

AU - Blumhorst, Catherine

AU - Brockmann, Knut

AU - Calder, Peter

AU - Cherman, Natasha

AU - Deardorff, Matthew A.

AU - Everman, David B.

AU - Golas, Gretchen

AU - Greenstein, Robert M.

AU - Kato, B. Maya

AU - Keppler-Noreuil, Kim M.

AU - Kuznetsov, Sergei A.

AU - Miyamoto, Richard

AU - Newman, Kurt

AU - Ng, David

AU - O'Brien, Kevin

AU - Rothenberg, Steven

AU - Schwartzentruber, Douglas J.

AU - Singhal, Virender

AU - Tirabosco, Roberto

AU - Upton, Joseph

AU - Wientroub, Shlomo

AU - Zackai, Elaine H.

AU - Hoag, Kimberly

AU - Whitewood-Neal, Tracey

AU - Robey, Pamela G.

AU - Schwartzberg, Pamela L.

AU - Darling, Thomas N.

AU - Tosi, Laura L.

AU - Mullikin, James C.

AU - Biesecker, Leslie G.

PY - 2011/8/18

Y1 - 2011/8/18

N2 - 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.)

AB - 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.)

UR - http://www.scopus.com/inward/record.url?scp=84860389181&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860389181&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1104017

DO - 10.1056/NEJMoa1104017

M3 - Article

C2 - 21793738

AN - SCOPUS:84860389181

VL - 365

SP - 611

EP - 619

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 7

ER -