title: Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy.
abstract: Mutations in the catalytic subunit of phosphoinositide 3-kinase (PIK3CA) and other PI3K-AKT pathway components have been associated with cancer and a wide spectrum of brain and body overgrowth. In the brain, the phenotypic spectrum of PIK3CA-related segmental overgrowth includes bilateral dysplastic megalencephaly, hemimegalencephaly and focal cortical dysplasia, the most common cause of intractable pediatric epilepsy. We generated mouse models expressing the most common activating Pik3ca mutations (H1047R and E545K) in developing neural progenitors. These accurately recapitulate all the key human pathological features including brain enlargement, cortical malformation, hydrocephalus and epilepsy, with phenotypic severity dependent on the mutant allele and its time of activation. Underlying mechanisms include increased proliferation, cell size and altered white matter. Notably, we demonstrate that acute 1 hr-suppression of PI3K signaling despite the ongoing presence of dysplasia has dramatic anti-epileptic benefit. Thus PI3K inhibitors offer a promising new avenue for effective anti-epileptic therapy for intractable pediatric epilepsy patients.
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Achira
authors.initials: A
authors.lastname: Roy
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Skibo
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Franck
authors.initials: F
authors.lastname: Kalume
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Boston, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Ni
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Sherri
authors.initials: S
authors.lastname: Rankin
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Cancer Biology, Dana Farber Cancer Institute, Boston, United States.
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Baker
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Millen
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D058627:Megalencephaly / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D050505:Mutant Proteins; D019869:Phosphatidylinositol 3-Kinases; C546639:Pik3ca protein, mouse
keywords: BKM120; PI3K; cortical dysplasia; epilepsy; human biology; medicine; megalencephaly; mouse; mouse models; neuroscience