title: Somatic activation of AKT3 causes hemispheric developmental brain malformations.
abstract: Hemimegalencephaly (HMG) is a developmental brain disorder characterized by an enlarged, malformed cerebral hemisphere, typically causing epilepsy that requires surgical resection. We studied resected HMG tissue to test whether the condition might reflect somatic mutations affecting genes critical to brain development. We found that two out of eight HMG samples showed trisomy of chromosome 1q, which encompasses many genes, including AKT3, a gene known to regulate brain size. A third case showed a known activating mutation in AKT3 (c.49G→A, creating p.E17K) that was not present in the patient's blood cells. Remarkably, the E17K mutation in AKT3 is exactly paralogous to E17K mutations in AKT1 and AKT2 recently discovered in somatic overgrowth syndromes. We show that AKT3 is the most abundant AKT paralog in the brain during neurogenesis and that phosphorylated AKT is abundant in cortical progenitor cells. Our data suggest that somatic mutations limited to the brain could represent an important cause of complex neurogenetic disease.
authors.affiliation: Department of Neurology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
authors.forename: Gilad D
authors.initials: GD
authors.lastname: Evrony
authors.forename: Xuyu
authors.initials: X
authors.lastname: Cai
authors.forename: Princess Christina
authors.initials: PC
authors.lastname: Elhosary
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Maria K
authors.initials: MK
authors.lastname: Lehtinen
authors.forename: L Benjamin
authors.initials: LB
authors.lastname: Hills
authors.forename: Erin L
authors.initials: EL
authors.lastname: Heinzen
authors.forename: Anthony
authors.initials: A
authors.lastname: Hill
authors.forename: R Sean
authors.initials: RS
authors.lastname: Hill
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Barry
authors.forename: Blaise F D
authors.initials: BF
authors.lastname: Bourgeois
authors.forename: James J
authors.initials: JJ
authors.lastname: Riviello
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.forename: Peter M
authors.initials: PM
authors.lastname: Black
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D054022:Cerebrum / Q000002:abnormalities* / Q000254:growth & development / Q000473:pathology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D004827:Epilepsy / Q000209:etiology / Q000473:pathology / Q000601:surgery; D006801:Humans; D054220:Malformations of Cortical Development / Q000150:complications / Q000235:genetics* / Q000473:pathology; D055495:Neurogenesis / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D014314:Trisomy / Q000235:genetics*
chemical_list: C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt