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

By Jeong Ho Lee, M. Huynh, J. Silhavy, Sangwoo Kim, Tracy J. Dixon-Salazar, A. Heiberg, Eric Scott, Vineet Bafna, K. J. Hill, Adrienne Collazo and 5 more. Nature Genetics, 2012

684 citations recorded by the source corpus.

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.

Subfields: Genetics, Molecular Biology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/2ce0e8d52090612aa3c1ce204b71b4126e327481

Citations in the corpus

• The Neurology of mTOR (2014, neutral): “More recently, several groups identified de novo somatic mutations of PI3K, AKT3, or mTOR genes in hemimegalencephaly, a condition associated with severe seizures (Lee et al., 2012; Poduri et al., 2012; Rivière et al., 2012).”