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

Abstract

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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Figure 1: MRI and mutation analysis in hemimegalencephaly.
Figure 2: Consistent de novo mutation burden across affected hemispheres.
Figure 3: The de novo mutations identified in HME correlate with hyperactive mTOR signaling.

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Acknowledgements

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sequencing support and analysis, D. Neelam (Sequenom) for technical support and W.B. Dobyns and M.L. Warman for sharing unpublished results.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.).

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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.

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Correspondence to Gary W Mathern or Joseph G Gleeson.

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Lee, J., Huynh, M., Silhavy, J. et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet 44, 941–945 (2012). https://doi.org/10.1038/ng.2329

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