Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia.

Abstract

Focal malformations of cortical development, including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are important causes of intractable childhood epilepsy. Using targeted and exome sequencing on DNA from resected brain samples and nonbrain samples from 53 patients with FCD or HME, we identified pathogenic germline and mosaic mutations in multiple PI3K/AKT pathway genes in 9 patients, and a likely pathogenic variant in 1 additional patient. Our data confirm the association of DEPDC5 with sporadic FCD but also implicate this gene for the first time in HME. Our findings suggest that modulation of the mammalian target of rapamycin pathway may hold promise for malformation-associated epilepsy.

• Authors: Alissa M D'Gama, Ying Geng, Javier A Couto, Beth Martin, Evan A Boyle, Christopher M LaCoursiere, Amer Hossain, Nicole E Hatem, Brenda J Barry, David J Kwiatkowski, Harry V Vinters, A James Barkovich, Jay Shendure, Gary W Mathern, Christopher A Walsh, Annapurna Poduri
• Journal: Annals of neurology (Ann Neurol) Vol. 77 Issue 4 Pg. 720-5 (Apr 2015) ISSN: 1531-8249 [Electronic] United States
• PMID: 25599672 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Neurological Association.

Chemical References

• DEPDC5 protein, human
• GTPase-Activating Proteins
• Repressor Proteins
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Cohort Studies
• GTPase-Activating Proteins
• Hemimegalencephaly (diagnosis, genetics)
• Humans
• Malformations of Cortical Development (diagnosis, genetics)
• Mutation (genetics)
• Phosphatidylinositol 3-Kinases (genetics)
• Proto-Oncogene Proteins c-akt (genetics)
• Repressor Proteins (genetics)
• Signal Transduction (genetics)
• TOR Serine-Threonine Kinases (genetics)