De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly |
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Authors: | Lee Jeong Ho Huynh My Silhavy Jennifer L Kim Sangwoo Dixon-Salazar Tracy Heiberg Andrew Scott Eric Bafna Vineet Hill Kiley J Collazo Adrienne Funari Vincent Russ Carsten Gabriel Stacey B Mathern Gary W Gleeson Joseph G |
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Affiliation: | Institute for Genomic Medicine, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA. |
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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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