Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.
We describe first cousin sibling pairs with focal epilepsy, one of each pair having focal cortical dysplasia (FCD) IIa. Linkage analysis and whole-exome sequencing identified a heterozygous germline frameshift mutation in the gene encoding nitrogen permease regulator-like 3 (NPRL3). NPRL3 is a component of GAP Activity Towards Rags 1, a negative regulator of the mammalian target of rapamycin complex 1 signaling pathway. Immunostaining of resected brain tissue demonstrated mammalian target of rapamycin activation. Screening of 52 unrelated individuals with FCD identified 2 additional patients with FCDIIa and germline NPRL3 mutations. Similar to DEPDC5, NPRL3 mutations may be considered as causal variants in patients with FCD or magnetic resonance imaging-negative focal epilepsy.
Bruce Lefroy Center for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.
Joe C
JC
Sim
Bioinformatics and Population Health and Immunity Divisions, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
Thomas
T
Scerri
Bruce Lefroy Center for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.
Miriam
M
Fanjul-Fernández
Bruce Lefroy Center for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.
Jessica R
JR
Riseley
Bruce Lefroy Center for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.
Greta
G
Gillies
Bruce Lefroy Center for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.
Kate
K
Pope
VUMC School of Medical Sciences, Amsterdam, The Netherlands.
Hanna
H
van Roozendaal
The Harry Perkins Institute of Medical Research, The Center for Medical Research, University of Western Australia, Perth, Australia.
Julian I
JI
Heng
The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.|University of Melbourne, Department of Radiology, Melbourne, Australia.|University of Melbourne, Department of Pediatrics, Melbourne, Australia.
Simone A
SA
Mandelstam
Bruce Lefroy Center for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.
George
G
McGillivray
Department of Anatomical Pathology, Royal Children's Hospital, Melbourne, Australia.
Duncan
D
MacGregor
Department of Neurology, Royal Children's Hospital, Melbourne, Australia.
Lakshminarayanan
L
Kannan
Neuroscience Research Group, Murdoch Childrens Research Institute, Melbourne, Australia.|Department of Neurosurgery, Royal Children's Hospital, Melbourne, Australia.
Wirginia
W
Maixner
Department of Neurology, Royal Children's Hospital, Melbourne, Australia.|Neuroscience Research Group, Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Department of Pediatrics, Melbourne, Australia.
A Simon
AS
Harvey
Bruce Lefroy Center for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Department of Pediatrics, Melbourne, Australia.
David J
DJ
Amor
Bruce Lefroy Center for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Department of Pediatrics, Melbourne, Australia.|Clinical Genetics, Austin Health, Melbourne, Australia.
Martin B
MB
Delatycki
Shriners Hospital Pediatric Research Center, Temple University, Philadelphia, PA.
Peter B
PB
Crino
Bioinformatics and Population Health and Immunity Divisions, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
Melanie
M
Bahlo
Bruce Lefroy Center for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Department of Pediatrics, Melbourne, Australia.
Paul J
PJ
Lockhart
Department of Neurology, Royal Children's Hospital, Melbourne, Australia.|Neuroscience Research Group, Murdoch Childrens Research Institute, Melbourne, Australia.|University of Melbourne, Department of Pediatrics, Melbourne, Australia.
Richard J
RJ
Leventer
D002648:Child; D002675:Child, Preschool; D004828:Epilepsies, Partial / Q000235:genetics*; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D065703:Malformations of Cortical Development, Group I / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D020690:GTPase-Activating Proteins; C543618:NPRL3 protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases