De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.
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.
Institute for Genomic Medicine, Rady Children's Hospital, University of California, San Diego, La Jolla, California, USA.
Jeong Ho
JH
Lee
My
M
Huynh
Jennifer L
JL
Silhavy
Sangwoo
S
Kim
Tracy
T
Dixon-Salazar
Andrew
A
Heiberg
Eric
E
Scott
Vineet
V
Bafna
Kiley J
KJ
Hill
Adrienne
A
Collazo
Vincent
V
Funari
Carsten
C
Russ
Stacey B
SB
Gabriel
Gary W
GW
Mathern
Joseph G
JG
Gleeson
D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009030:Mosaicism; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C491754:AKT3 protein, human