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Ann Neurol. 2016 Jan;79(1):132-7. doi: 10.1002/ana.24502. Epub 2015 Dec 12.

Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.

Author information

1
Bruce Lefroy Center for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia.
2
Bioinformatics and Population Health and Immunity Divisions, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
3
Department of Medical Biology, The University of Melbourne, Melbourne, Australia.
4
VUMC School of Medical Sciences, Amsterdam, The Netherlands.
5
The Harry Perkins Institute of Medical Research, The Center for Medical Research, University of Western Australia, Perth, Australia.
6
The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.
7
University of Melbourne, Department of Radiology, Melbourne, Australia.
8
University of Melbourne, Department of Pediatrics, Melbourne, Australia.
9
Department of Anatomical Pathology, Royal Children's Hospital, Melbourne, Australia.
10
Department of Neurology, Royal Children's Hospital, Melbourne, Australia.
11
Neuroscience Research Group, Murdoch Childrens Research Institute, Melbourne, Australia.
12
Department of Neurosurgery, Royal Children's Hospital, Melbourne, Australia.
13
Clinical Genetics, Austin Health, Melbourne, Australia.
14
Shriners Hospital Pediatric Research Center, Temple University, Philadelphia, PA.

Abstract

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.

PMID:
26285051
DOI:
10.1002/ana.24502
[Indexed for MEDLINE]

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