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Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3 |
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| Authors: | Miriam Fanjul‐Fernández PhD Jessica R. Riseley BSc Greta Gillies MSci Kate Pope BSc Hanna van Roozendaal Bsc Julian I. Heng PhD Simone A. Mandelstam MBChB George McGillivray MBChB Duncan MacGregor MBBS PhD Lakshminarayanan Kannan MBBS Wirginia Maixner MBBS A. Simon Harvey MBBS MD David J. Amor MBBS PhD Martin B. Delatycki MBBS PhD Peter B. Crino MD PhD Melanie Bahlo PhD Richard J. Leventer MBBS PhD |
| Affiliation: | 1. Bruce Lefroy Center for Genetic Health Research, Murdoch Childrens Research Institute, Melbourne, Australia;2. VUMC School of Medical Sciences, Amsterdam, The Netherlands;3. The Harry Perkins Institute of Medical Research, The Center for Medical Research, University of Western Australia, Perth, Australia;4. The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia;5. University of Melbourne, Department of Radiology, Melbourne, Australia;6. University of Melbourne, Department of Pediatrics, Melbourne, Australia;7. Department of Anatomical Pathology, Royal Children's Hospital, Melbourne, Australia;8. Department of Neurology, Royal Children's Hospital, Melbourne, Australia;9. Neuroscience Research Group, Murdoch Childrens Research Institute, Melbourne, Australia;10. Department of Neurosurgery, Royal Children's Hospital, Melbourne, Australia;11. Clinical Genetics, Austin Health, Melbourne, Australia;12. Shriners Hospital Pediatric Research Center, Temple University, Philadelphia, PA;13. Bioinformatics and Population Health and Immunity Divisions, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia;14. Department of Medical Biology, The University of Melbourne, Melbourne, Australia |
| 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. ANN NEUROL 2016;79:132–137 |
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