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Updated: Jun 24, 2025

Spatial and Temporal Analysis of Active ERK in the C. elegans Germline
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Spatial and Temporal Analysis of Active ERK in the C. elegans Germline

Published on: November 29, 2016

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Focal cortical dysplasia II caused by brain somatic mutation of IRS-1 is associated with ERK signaling pathway

Xiao Li1,2,3, Tianshuang Wang4, Nana Liu1,2,3

  • 1Department of Pediatrics, Peking University First Hospital, No. 1 Xi'an Men Street, West District, Beijing 100034, China.

Cerebral Cortex (New York, N.Y. : 1991)
|June 5, 2024
PubMed

Insights

A novel IRS-1 gene variant causes focal cortical dysplasia type II by activating the ERK pathway, leading to abnormal neuron development. Targeting ERK, not mTOR, may treat these cases.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Focal cortical dysplasia type II (FCDII) involves somatic mutations, often in the mTOR pathway.
  • Unidentified mutations suggest novel pathogenic genes or pathways in FCDII.
  • A prior study identified a candidate IRS-1 c.1791dupG somatic variant in FCDII.

Purpose of the Study:

  • To investigate the role of the IRS-1 c.1791dupG variant in FCDII pathogenesis.
  • To explore the effects of the variant on neuronal development and signaling pathways.
  • To identify potential therapeutic targets for FCDII.

Main Methods:

  • In vitro overexpression studies in 293T and SH-SY5Y cells.
  • In vivo evaluation using in utero electroporation in fetal brains.
  • Assessment of neuronal migration, morphology, network integrity, and signaling pathway activity (p-ERK, MAPK).

Main Results:

  • The IRS-1 c.1791dupG variant caused hyperactivity of p-ERK and increased cell volume, implicating the MAPK pathway.
  • In vivo, the variant led to abnormal neuron migration, cytomegaly, and network hyperexcitability.
  • The ERK inhibitor GDC-0994, but not the mTOR inhibitor rapamycin, rescued the observed neuronal defects.

Conclusions:

  • The ERK signaling pathway is directly implicated in the pathogenesis of FCDII.
  • The IRS-1 c.1791dupG variant contributes to FCDII through MAPK pathway activation.
  • Targeting the ERK pathway offers a potential therapeutic strategy for specific FCDII cases.
Keywords:
epilepsyfocal cortical dysplasiainsulin receptor substrate 1malformations of cortical developmentsomatic mutation

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