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

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


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Child, Preschool
  • Epilepsies, Partial / genetics*
  • Epilepsy / genetics*
  • Female
  • GTPase-Activating Proteins / genetics*
  • Humans
  • Male
  • Malformations of Cortical Development, Group I / genetics*
  • Mutation
  • Pedigree
  • Signal Transduction
  • TOR Serine-Threonine Kinases


  • GTPase-Activating Proteins
  • NPRL3 protein, human
  • MTOR protein, human
  • TOR Serine-Threonine Kinases

Supplementary concepts

  • Focal cortical dysplasia of Taylor