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

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 +15 more·2016·Annals of Neurology

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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Crossref · 10.1002/ana.24547

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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.
Venue
Annals of Neurology
Publisher
Wiley
Published
2015-12-12
Volume
79
Issue
1
Pages
120-131
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
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
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 › Psychiatry and Mental health › Epilepsy research and treatment
  • Health Sciences › Medicine › Physiology › 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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