Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy

Achira Roy, Jonathan Skibo, Franck Kalume, Jing Ni, Sherri Rankin, Yiling Lu, William B. Dobyns, Gordon Mills, Jean J. Zhao, Suzanne J. Baker, Kathleen J. Millen

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere12703
JournaleLife
Volume4
Issue numberDECEMBER2015
DOIs
StatePublished - Dec 3 2015
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinases
Epilepsy
Brain
Pediatrics
Megalencephaly
Malformations of Cortical Development
Mutation
1-Phosphatidylinositol 4-Kinase
Cell proliferation
Hydrocephalus
Phosphatidylinositols
Cell Size
Catalytic Domain
Phosphotransferases
Chemical activation
Alleles
Neoplasms
Drug Resistant Epilepsy
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Roy, A., Skibo, J., Kalume, F., Ni, J., Rankin, S., Lu, Y., ... Millen, K. J. (2015). Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. eLife, 4(DECEMBER2015), [e12703]. https://doi.org/10.7554/eLife.12703

Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. / Roy, Achira; Skibo, Jonathan; Kalume, Franck; Ni, Jing; Rankin, Sherri; Lu, Yiling; Dobyns, William B.; Mills, Gordon; Zhao, Jean J.; Baker, Suzanne J.; Millen, Kathleen J.

In: eLife, Vol. 4, No. DECEMBER2015, e12703, 03.12.2015.

Research output: Contribution to journalArticle

Roy, A, Skibo, J, Kalume, F, Ni, J, Rankin, S, Lu, Y, Dobyns, WB, Mills, G, Zhao, JJ, Baker, SJ & Millen, KJ 2015, 'Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy', eLife, vol. 4, no. DECEMBER2015, e12703. https://doi.org/10.7554/eLife.12703
Roy A, Skibo J, Kalume F, Ni J, Rankin S, Lu Y et al. Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. eLife. 2015 Dec 3;4(DECEMBER2015). e12703. https://doi.org/10.7554/eLife.12703
Roy, Achira ; Skibo, Jonathan ; Kalume, Franck ; Ni, Jing ; Rankin, Sherri ; Lu, Yiling ; Dobyns, William B. ; Mills, Gordon ; Zhao, Jean J. ; Baker, Suzanne J. ; Millen, Kathleen J. / Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. In: eLife. 2015 ; Vol. 4, No. DECEMBER2015.
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