Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy

Date

2016

Authors

Ricos, M.G.
Hodgson, B.L.
Pippucci, T.
Saidin, A.
Ong, Y.S.
Heron, S.E.
Licchetta, L.
Bisulli, F.
Bayly, M.A.
Hughes, J.

Editors

Advisors

Journal Title

Journal ISSN

Volume Title

Type:

Journal article

Citation

Annals of Neurology, 2016; 79(1):120-131

Statement of Responsibility

Michael G. Ricos, Bree L. Hodgson, Tommaso Pippucci, Akzam Saidin, Yeh Sze Ong, Sarah E. Heron, Laura Licchetta, Francesca Bisulli, Marta A. Bayly, James Hughes, Sara Baldassari, Flavia Palombo, Epilepsy Electroclinical Study Group, Margherita Santucci, Stefano Meletti, Samuel F. Berkovic, Guido Rubboli, Paul Q. Thomas, Ingrid E. Scheffer, Paolo Tinuper, Joel Geoghegan, Andreas W. Schreiber, and Leanne M. Dibbens

Conference Name

Abstract

Focal epilepsies are the most common form observed and have not generally been considered to be genetic in origin. Recently, we identified mutations in DEPDC5 as a cause of familial focal epilepsy. In this study, we investigated whether mutations in the mammalian target of rapamycin (mTOR) regulators, NPRL2 and NPRL3, also contribute to cases of focal epilepsy.We used targeted capture and next-generation sequencing to analyze 404 unrelated probands with focal epilepsy. We performed exome sequencing on two families with multiple members affected with focal epilepsy and linkage analysis on one of these.In our cohort of 404 unrelated focal epilepsy patients, we identified five mutations in NPRL2 and five in NPRL3. Exome sequencing analysis of two families with focal epilepsy identified NPRL2 and NPRL3 as the top candidate-causative genes. Some patients had focal epilepsy associated with brain malformations. We also identified 18 new mutations in DEPDC5.We have identified NPRL2 and NPRL3 as two new focal epilepsy genes that also play a role in the mTOR-signaling pathway. Our findings show that mutations in GATOR1 complex genes are the most significant cause of familial focal epilepsy identified to date, including cases with brain malformations. It is possible that deregulation of cellular growth control plays a more important role in epilepsy than is currently recognized.

School/Discipline

Dissertation Note

Provenance

Description

Version of Record online: 12 DEC 2015 Data source: Supporting information, http://onlinelibrary.wiley.com/doi/10.1002/ana.24547/abstract#footer-support-info

Access Status

Rights

© 2015 American Neurological Association

License

Call number

Persistent link to this record