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


CONCLUSIONS
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.
Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.|Molecular Neurogenomics Research Laboratory, Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
Michael G
MG
Ricos
Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.|Molecular Neurogenomics Research Laboratory, Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
Bree L
BL
Hodgson
Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi University Hospital, Bologna, Italy.|Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Tommaso
T
Pippucci
Novocraft Technologies Sdn Bhd, Selangor, Malaysia.
Akzam
A
Saidin
Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.|Molecular Neurogenomics Research Laboratory, Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
Yeh Sze
YS
Ong
Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.|Molecular Neurogenomics Research Laboratory, Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
Sarah E
SE
Heron
IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.|Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Laura
L
Licchetta
IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.|Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Francesca
F
Bisulli
Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.|Molecular Neurogenomics Research Laboratory, Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
Marta A
MA
Bayly
School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.
James
J
Hughes
Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi University Hospital, Bologna, Italy.|Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Sara
S
Baldassari
Medical Genetics Unit, Polyclinic Sant'Orsola-Malpighi University Hospital, Bologna, Italy.|Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Flavia
F
Palombo
IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.|Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Margherita
M
Santucci
Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, AUSL Modena, Modena, Italy.
Stefano
S
Meletti
Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Victoria, Australia.
Samuel F
SF
Berkovic
Danish Epilepsy Center, Filadelfia/University of Copenhagen, Dianalund, Denmark.|IRCCS Institute of Neurological Sciences, Neurology Unit, Bellaria Hospital, Bologna, Italy.
Guido
G
Rubboli
School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.
Paul Q
PQ
Thomas
Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Victoria, Australia.|Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia.|Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia.
Ingrid E
IE
Scheffer
IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.|Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Paolo
P
Tinuper
ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
Joel
J
Geoghegan
School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia.|ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
Andreas W
AW
Schreiber
Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.|Molecular Neurogenomics Research Laboratory, Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
Leanne M
LM
Dibbens
D004828:Epilepsies, Partial / Q000235:genetics*; D059472:Exome; D020690:GTPase-Activating Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C000590398:DEPDC5 protein, human; D020690:GTPase-Activating Proteins; D046912:Multiprotein Complexes; C492816:NPRL2 protein, human; C543618:NPRL3 protein, human; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases