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Objective  Focal cortical dysplasias (FCDs) are an important cause of drug‐resistant epilepsy. In this work, we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II.    Methods  We used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative polymerase chain reaction, in situ hybridization, luciferase reporter assays, and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study.    Results  hsa‐let‐7f ( p  = 0.039), hsa‐miR‐31 ( p  = 0.0078), and hsa‐miR34a ( p  = 0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification,  NEUROG2  ( p  < 0.05), was upregulated. We also found that the  RND2  gene, a  NEUROG2‐ target, is upregulated ( p  < 0.001). In vitro experiments showed that hsa‐miR‐34a downregulates  NEUROG2  by binding to its 5′‐untranslated region. Moreover, we observed strong nuclear expression of  NEUROG2  in balloon cells and dysmorphic neurons and found that 28.5% of our patients presented brain somatic mutations in genes of the mTOR pathway.    Interpretation  Our findings suggest a new molecular mechanism, in which  NEUROG2  has a pivotal and central role in the pathogenesis of FCD type II. In this way, we found that the downregulation of hsa‐miR‐34a leads to upregulation of  NEUROG2 , and consequently to overexpression of the  RND2  gene. These findings indicate that a faulty coupling in neuronal differentiation and migration mechanisms may explain the presence of aberrant cells and complete dyslamination in FCD type II. Ann Neurol 2018;83:623–635

Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia