Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

Alissa M D'Gama; Mollie B Woodworth; Amer A Hossain; Sara Bizzotto; Nicole E Hatem; Christopher M LaCoursiere; Imad Najm; Zhong Ying; Edward Yang; A James Barkovich; David J Kwiatkowski; Harry V Vinters; Joseph R Madsen; Gary W Mathern; Ingmar Blümcke; Annapurna Poduri; Christopher A Walsh

doi:10.1016/j.celrep.2017.11.106

Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

Cell Rep. 2017 Dec 26;21(13):3754-3766. doi: 10.1016/j.celrep.2017.11.106.

Authors

Alissa M D'Gama¹, Mollie B Woodworth¹, Amer A Hossain¹, Sara Bizzotto¹, Nicole E Hatem¹, Christopher M LaCoursiere², Imad Najm³, Zhong Ying³, Edward Yang⁴, A James Barkovich⁵, David J Kwiatkowski⁶, Harry V Vinters⁷, Joseph R Madsen⁸, Gary W Mathern⁹, Ingmar Blümcke¹⁰, Annapurna Poduri¹¹, Christopher A Walsh¹²

Affiliations

¹ Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
² Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ Epilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA.
⁴ Department of Radiology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Radiology, Harvard Medical School, Boston, MA 02115, USA.
⁵ Departments of Radiology and Diagnostic Imaging, Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁷ Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ Department of Neurosurgery, Boston Children's Hospital, Boston, MA, USA.
⁹ Departments of Neurosurgery and Psychiatry and Biobehavioral Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Epilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Neuropathology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
¹¹ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
¹² Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. Electronic address: [email protected].

Abstract

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.

Keywords: brain malformations; cortical development; epilepsy; excitatory neurons; focal cortical dysplasia; hemimegalancephaly; mTOR pathway; next-generation sequencing; single-cell sequencing; somatic mutations.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Lineage
Class I Phosphatidylinositol 3-Kinases / genetics
Hemimegalencephaly / genetics
Hemimegalencephaly / pathology
High-Throughput Nucleotide Sequencing
Humans
Malformations of Cortical Development / genetics*
Mice
Mutation / genetics*
Neurons / metabolism
Neurons / pathology
Signal Transduction*
Stem Cells / metabolism*
TOR Serine-Threonine Kinases / metabolism*
Telencephalon / pathology*

Substances

Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding