PMID- 22729223
OWN - NLM
STAT- MEDLINE
DCOM- 20121009
LR  - 20231120
IS  - 1546-1718 (Electronic)
IS  - 1061-4036 (Print)
IS  - 1061-4036 (Linking)
VI  - 44
IP  - 8
DP  - 2012 Jun 24
TI  - De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause 
      hemimegalencephaly.
PG  - 941-5
LID - 10.1038/ng.2329 [doi]
AB  - 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.
FAU - Lee, Jeong Ho
AU  - Lee JH
AD  - Institute for Genomic Medicine, Rady Children's Hospital, University of 
      California, San Diego, La Jolla, California, USA.
FAU - Huynh, My
AU  - Huynh M
FAU - Silhavy, Jennifer L
AU  - Silhavy JL
FAU - Kim, Sangwoo
AU  - Kim S
FAU - Dixon-Salazar, Tracy
AU  - Dixon-Salazar T
FAU - Heiberg, Andrew
AU  - Heiberg A
FAU - Scott, Eric
AU  - Scott E
FAU - Bafna, Vineet
AU  - Bafna V
FAU - Hill, Kiley J
AU  - Hill KJ
FAU - Collazo, Adrienne
AU  - Collazo A
FAU - Funari, Vincent
AU  - Funari V
FAU - Russ, Carsten
AU  - Russ C
FAU - Gabriel, Stacey B
AU  - Gabriel SB
FAU - Mathern, Gary W
AU  - Mathern GW
FAU - Gleeson, Joseph G
AU  - Gleeson JG
LA  - eng
GR  - P30 NS047101/NS/NINDS NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - R01 NS048453/NS/NINDS NIH HHS/United States
GR  - R01 NS038992/NS/NINDS NIH HHS/United States
GR  - R01 NS083823/NS/NINDS NIH HHS/United States
GR  - U54 HG003067/HG/NHGRI NIH HHS/United States
GR  - P30NS047101/NS/NINDS NIH HHS/United States
GR  - U54HG003067/HG/NHGRI NIH HHS/United States
GR  - R01 NS041537/NS/NINDS NIH HHS/United States
GR  - R01 NS052455/NS/NINDS NIH HHS/United States
GR  - P01 HD070494/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120624
PL  - United States
TA  - Nat Genet
JT  - Nature genetics
JID - 9216904
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.11.1 (AKT3 protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Child, Preschool
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - DNA Mutational Analysis
MH  - Exome
MH  - Female
MH  - Humans
MH  - Infant
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Malformations of Cortical Development/*genetics/metabolism/pathology
MH  - Mosaicism
MH  - *Mutation, Missense
MH  - Phosphatidylinositol 3-Kinases/*genetics
MH  - Proto-Oncogene Proteins c-akt/*genetics
MH  - Signal Transduction/genetics
MH  - TOR Serine-Threonine Kinases/*genetics
PMC - PMC4417942
MID - NIHMS683085
EDAT- 2012/06/26 06:00
MHDA- 2012/10/10 06:00
PMCR- 2015/05/04
CRDT- 2012/06/26 06:00
PHST- 2012/03/30 00:00 [received]
PHST- 2012/05/24 00:00 [accepted]
PHST- 2012/06/26 06:00 [entrez]
PHST- 2012/06/26 06:00 [pubmed]
PHST- 2012/10/10 06:00 [medline]
PHST- 2015/05/04 00:00 [pmc-release]
AID - ng.2329 [pii]
AID - 10.1038/ng.2329 [doi]
PST - epublish
SO  - Nat Genet. 2012 Jun 24;44(8):941-5. doi: 10.1038/ng.2329.