Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/98947
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Type: Journal article
Title: Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy
Author: Ricos, M.
Hodgson, B.
Pippucci, T.
Saidin, A.
Ong, Y.
Heron, S.
Licchetta, L.
Bisulli, F.
Bayly, M.
Hughes, J.
Baldassari, S.
Palombo, F.
Epilepsy Electroclinical Study Group
Santucci, M.
Meletti, S.
Berkovic, S.
Rubboli, G.
Thomas, P.
Scheffer, I.
Tinuper, P.
et al.
Citation: Annals of Neurology, 2016; 79(1):120-131
Publisher: Wiley
Issue Date: 2016
ISSN: 0364-5134
1531-8249
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
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.
Keywords: Epilepsy Electroclinical Study Group; Humans; Epilepsies, Partial; Multiprotein Complexes; GTPase-Activating Proteins; Tumor Suppressor Proteins; Repressor Proteins; Gene Expression Profiling; Pedigree; Sequence Analysis, DNA; Signal Transduction; Mutation; TOR Serine-Threonine Kinases; Exome
Description: Version of Record online: 12 DEC 2015
Rights: © 2015 American Neurological Association
RMID: 0030037968
DOI: 10.1002/ana.24547
Grant ID: http://purl.org/au-research/grants/nhmrc/628952
http://purl.org/au-research/grants/nhmrc/1006110
http://purl.org/au-research/grants/nhmrc/1016715
http://purl.org/au-research/grants/nhmrc/1032603
Appears in Collections:Pathology publications

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