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An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors

Eli J Rogers1, Reem Jada1, Kinneret Schragenheim-Rozales1

  • 1Technion Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel.

Frontiers in Molecular Neuroscience
|March 8, 2019
PubMed

Insights

A mutation in IQSEC2 causes intellectual disability, autism, and epilepsy by disrupting protein binding and activating a key signaling pathway. Mouse models show reduced synaptic function and behavioral deficits, suggesting new therapeutic targets.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Intellectual disability, autism, and epilepsy are complex neurodevelopmental disorders.
  • The IQSEC2 gene and its associated mutations are implicated in these conditions.
  • Understanding the molecular basis of IQSEC2 mutations is crucial for developing effective therapies.

Purpose of the Study:

  • To elucidate the molecular pathophysiology of the A350V mutation in IQSEC2.
  • To identify potential drug targets for treating neurodevelopmental disorders caused by this mutation.

Main Methods:

  • Investigated the effect of the A350V mutation on apocalmodulin binding to IQSEC2.
  • Assessed the guanine nucleotide exchange factor (GEF) activity of mutated IQSEC2 and its impact on Arf6.
  • Utilized a CRISPR-generated mouse model to study the mutation's effects on hippocampal GluA2 AMPA receptor surface expression and synaptic transmission.
  • Evaluated behavioral phenotypes in mutant mice, including activity levels, social behavior, and learning.

Main Results:

  • The A350V mutation impairs apocalmodulin binding to IQSEC2.
  • This mutation leads to constitutive activation of IQSEC2's GEF activity, increasing active Arf6 production.
  • Mutant mice exhibit reduced surface expression of GluA2 AMPA receptors and impaired basal synaptic transmission in the hippocampus.
  • A350V IQSEC2 mutant mice display increased activity, abnormal social behavior, and learning deficits.

Conclusions:

  • The A350V mutation in IQSEC2 disrupts protein interactions and signaling pathways, leading to neurophysiological and behavioral abnormalities.
  • These findings provide a mechanistic model for IQSEC2-related neurodevelopmental disorders.
  • The study highlights potential therapeutic targets for a personalized, precision medicine approach to these conditions.
Keywords:
AMPAArf6GEFIQ domainIQSEC2autismcalmodulinintellectual disability

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