Cited by 247Epilepsy research and treatmentTuberous Sclerosis Complex ResearchGenetics and Neurodevelopmental Disorders

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

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Ricos, Michael G., Hodgson, Bree L., Pippucci, Tommaso, Saidin, Akzam, Ong, Yeh Sze, Heron, Sarah E., Licchetta, Laura, Bisulli, Francesca, Bayly, Marta A., Hughes, James, Baldassari, Sara, Palombo, Flavia, Epilepsy Electroclinical Study Group, Santucci, Margherita, Meletti, Stefano, Berkovic, Samuel F., Rubboli, Guido, Thomas, Paul Q., Scheffer, Ingrid E., Tinuper, Paolo, Geoghegan, Joel, Schreiber, Andreas W., Dibbens, Leanne M.·2016·Annals of Neurology

DOI 10.1002/ana.24547

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Abstract

Objective: 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. Methods: 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. Results: 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 . Interpretation: 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. ANN NEUROL 2016;79:120–131

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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., Baldassari, S., Palombo, F., Epilepsy Electroclinical Study Group, Santucci, M., Meletti, S., Berkovic, S. F., Rubboli, G., Thomas, P. Q., Scheffer, I. E., Tinuper, P., Geoghegan, J., Schreiber, A. W., & Dibbens, L. M.
Affiliations: University of South Australia (AU)
IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
Novocraft Technologies Sdn Bhd Selangor Malaysia
Istituto delle Scienze Neurologiche di Bologna (IT)
The University of Adelaide (AU)
University of Modena and Reggio Emilia (IT)
The University of Melbourne (AU)
University of Copenhagen (DK)
Royal Children's Hospital (AU)
South Australia Pathology (AU)
Corresponding author: Dibbens, Leanne M.
ORCID: Ricos, Michael G.
Pippucci, Tommaso
Saidin, Akzam
Heron, Sarah E.
Licchetta, Laura
Bisulli, Francesca
Bayly, Marta A.
Hughes, James
Baldassari, Sara
Palombo, Flavia
Santucci, Margherita
Meletti, Stefano
Berkovic, Samuel F.
Rubboli, Guido
Scheffer, Ingrid E.
Tinuper, Paolo
Schreiber, Andreas W.
Dibbens, Leanne M.
Venue: Annals of Neurology
Publisher: Wiley
Published: 2015-12-12
Volume: 79
Issue: 1
Pages: 120-131
ISSN: 0364-5134 (ISSN-L)
1531-8249
DOI: 10.1002/ana.24547
OpenAlex: W2302804942
Cited by: 246
References: 50
Citations by year: 2026: 14 · 2025: 23 · 2024: 21 · 2023: 25 · 2022: 24 · 2021: 23 · 2020: 41 · 2019: 19 · 2018: 23 · 2017: 20 · 2016: 13
FWCI: 15.14
Type: journal article
Language: en
Open access: green
hdl.handle.net
Licence: cc-by
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Annals of Neurology (publishedVersion)
PubMed (publishedVersion)
Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
Florence Research (University of Florence) (submittedVersion)
IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
Funders: Australian Cancer Research Foundation
National Health and Medical Research Council
National Medical Research Council
Topics: Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: focal epilepsy, NPRL2, NPRL3, mTOR signaling, GATOR1 complex, genetic epilepsy, brain malformations, familial epilepsy
MeSH terms: Mechanistic Target of Rapamycin Complex 1, Epilepsies, Partial, Humans, Mutation, Pedigree, Repressor Proteins, Signal Transduction, Sequence Analysis, DNA, GTPase-Activating Proteins, Gene Expression Profiling, Tumor Suppressor Proteins, Multiprotein Complexes, TOR Serine-Threonine Kinases, Exome

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

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