Letter | Published:

De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly

Nature Genetics volume 44, pages 941945 (2012) | Download Citation


De novo somatic mutations in focal areas are well documented in diseases such as neoplasia but are rarely reported in malformation of the developing brain. Hemimegalencephaly (HME) is characterized by overgrowth of either one of the two cerebral hemispheres. The molecular etiology of HME remains a mystery. The intractable epilepsy that is associated with HME can be relieved by the surgical treatment hemispherectomy, allowing sampling of diseased tissue. Exome sequencing and mass spectrometry analysis in paired brain-blood samples from individuals with HME (n = 20 cases) identified de novo somatic mutations in 30% of affected individuals in the PIK3CA, AKT3 and MTOR genes. A recurrent PIK3CA c.1633G>A mutation was found in four separate cases. Identified mutations were present in 8–40% of sequenced alleles in various brain regions and were associated with increased neuronal S6 protein phosphorylation in the brains of affected individuals, indicating aberrant activation of mammalian target of rapamycin (mTOR) signaling. Thus HME is probably a genetically mosaic disease caused by gain of function in phosphatidylinositol 3-kinase (PI3K)-AKT3-mTOR signaling.

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We thank J. Meerloo at the UCSD Neurosciences Core for microscopy services (supported by the US National Institute of Neurological Disorders and Stroke; P30NS047101), the Genomics Core at Cedars-Sinai Medical Center, the Broad Institute (supported by the US National Human Genome Research Institute; U54HG003067 to E. Lander) for sequencing support and analysis, D. Neelam (Sequenom) for technical support and W.B. Dobyns and M.L. Warman for sharing unpublished results. This work was supported by grants from the Daland Fellowship from the American Philosophical Society (to J.H.L.), the US National Institutes of Health (R01 NS038992 to G.W.M. and R01 NS048453, R01 NS052455, R01 NS041537 and P01 HD070494), the Simons Foundation Autism Research Initiative and the Howard Hughes Medical Institute (to J.G.G.).

Author information

Author notes

    • Jeong Ho Lee

    Present address: Translational Neurogenetics Laboratory, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

    • Gary W Mathern
    •  & Joseph G Gleeson

    These authors jointly directed this work.


  1. Institute for Genomic Medicine, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA.

    • Jeong Ho Lee
    • , Jennifer L Silhavy
    • , Tracy Dixon-Salazar
    • , Andrew Heiberg
    • , Eric Scott
    • , Kiley J Hill
    • , Adrienne Collazo
    •  & Joseph G Gleeson
  2. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Jeong Ho Lee
    • , Jennifer L Silhavy
    • , Tracy Dixon-Salazar
    • , Andrew Heiberg
    • , Eric Scott
    • , Kiley J Hill
    • , Adrienne Collazo
    •  & Joseph G Gleeson
  3. Department of Neurosurgery, Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

    • My Huynh
    •  & Gary W Mathern
  4. Department of Psychiatry and Biobehavioral Sciences, Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

    • My Huynh
    •  & Gary W Mathern
  5. Department of Computer Sciences, School of Engineering, University of California, San Diego, La Jolla, California, USA.

    • Sangwoo Kim
    •  & Vineet Bafna
  6. Institute for Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Vincent Funari
  7. Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

    • Vincent Funari
  8. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Carsten Russ
    •  & Stacey B Gabriel


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J.H.L. and J.L.S. organized the project and performed genetic studies. K.J.H., A.C. and J.H.L. recruited subjects. J.H.L., M.H. and T.D.-S. performed immunostaining. C.R. and S.B.G. generated and interpreted exome results. S.K., A.H., E.S., V.B. and J.H.L. performed JointSNVMix analysis. V.F. and J.H.L. oversaw SNP genotyping and analyzed CNVs. G.W.M. performed surgeries and managed samples along with M.H. G.W.M. and J.G.G. conceived of the project and oversaw data collection and manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Gary W Mathern or Joseph G Gleeson.

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