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

Ann Neurol. 2016 Jan;79(1):120-31. doi: 10.1002/ana.24547.

Michael G Ricos ¹ ² ³, Bree L Hodgson ¹ ² ³, Tommaso Pippucci ⁴ ⁵, Akzam Saidin ⁶, Yeh Sze Ong ¹ ² ³, Sarah E Heron ¹ ² ³, Laura Licchetta ⁷ ⁸, Francesca Bisulli ⁷ ⁸, Marta A Bayly ¹ ² ³, James Hughes ⁹, Sara Baldassari ⁴ ⁵, Flavia Palombo ⁴ ⁵, Epilepsy Electroclinical Study Group, Margherita Santucci ⁷ ⁸, Stefano Meletti ¹⁰, Samuel F Berkovic ¹¹, Guido Rubboli ¹² ¹³, Paul Q Thomas ⁹, Ingrid E Scheffer ¹¹ ¹⁴ ¹⁵, Paolo Tinuper ⁷ ⁸, Joel Geoghegan ¹⁶, Andreas W Schreiber ⁹ ¹⁶, Leanne M Dibbens ¹ ² ³

Affiliations

1 Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
2 Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
3 Molecular Neurogenomics Research Laboratory, Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
4 Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi University Hospital, Bologna, Italy.
5 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
6 Novocraft Technologies Sdn Bhd, Selangor, Malaysia.
7 IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
8 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
9 School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.
10 Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, AUSL Modena, Modena, Italy.
11 Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Victoria, Australia.
12 Danish Epilepsy Center, Filadelfia/University of Copenhagen, Dianalund, Denmark.
13 IRCCS Institute of Neurological Sciences, Neurology Unit, Bellaria Hospital, Bologna, Italy.
14 Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.
15 Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.
16 ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.

PMID: 26505888 DOI: 10.1002/ana.24547

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.

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