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Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical

Ashleigh E Schaffer1,2, Martin W Breuss3, Ahmet Okay Caglayan4,5

  • 1Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA. ashleigh.schaffer@case.edu.

Nature Genetics
|July 18, 2018
PubMed

Insights

Biallelic mutations in CTNNA2 cause a new pachygyria syndrome. This study reveals alphaN-catenin (CTNNA2) represses ARP2/3 activity, crucial for neuronal development and migration.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Genetics

Background:

  • Neuronal migration defects, such as pachygyria, represent severe human developmental brain abnormalities.
  • Catenin family proteins play critical roles in cellular structure and signaling, but their specific roles in human brain development are not fully elucidated.

Purpose of the Study:

  • To identify the genetic cause of a distinct recessive form of pachygyria.
  • To investigate the function of alphaN-catenin (CTNNA2) in neuronal development and its role in actin regulation.

Main Methods:

  • Genetic analysis of patients with pachygyria to identify causative mutations.
  • In vitro studies using recombinant proteins to assess alphaN-catenin's interaction with actin and its effect on ARP2/3 activity.
  • Cellular assays to evaluate the impact of CTNNA2 loss on neuronal morphology and migration.

Main Results:

  • Biallelic truncating mutations in CTNNA2 were identified in patients with a novel recessive pachygyria syndrome.
  • Loss of CTNNA2 in neurons resulted in impaired neurite stability and migration.
  • AlphaN-catenin directly interacts with actin and represses ARP2/3 actin-branching activity, independent of beta-catenin signaling.

Conclusions:

  • CTNNA2 mutations cause a new pachygyria syndrome linked to aberrant actin regulation.
  • AlphaN-catenin is a key repressor of ARP2/3 activity in neurons, essential for proper brain development.
  • Targeting ARP2/3 activity may offer therapeutic potential for CTNNA2-related disorders.

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