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

Authors
 Jeong Ho Lee ; My Huynh ; Gary W Mathern & Joseph G Gleeson ; Stacey B Gabriel ; Carsten Russ ; Vincent Funari ; Adrienne Collazo ; Kiley J Hill ; Vineet Bafna ; Eric Scott ; Andrew Heiberg ; Tracy Dixon-Salazar ; Sangwoo Kim ; Jennifer L Silhavy 
Citation
 NATURE GENETICS, Vol.44(8) : 941~945, 2012 
Journal Title
 NATURE GENETICS 
ISSN
 1061-4036 
Issue Date
2012
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.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/91504
DOI
10.1038/ng.2329
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Life Science
Yonsei Authors
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Link
 http://www.nature.com/ng/journal/v44/n8/full/ng.2329.html
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