Journal
NATURE GENETICS
Volume 50, Issue 8, Pages 1093-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-018-0166-0
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Funding
- NIH [R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101]
- Qatar National Research Fund [6-1463-351]
- Simons Foundation Autism Research Initiative
- Howard Hughes Medical Institute
- A.P. Giannini Fellowship
- NIH Pathway to Independence Award [R00HD082337]
- 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation
- Yale Center for Mendelian Disorders [UMIHG008900, UMIHG006504]
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Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding alpha N-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The alpha N-catenin paralog, alpha E-catenin, acts as a switch regulating the balance between beta-catenin and Arp2/3 actin filament activities(1). Loss of alpha N-catenin did not affect beta-catenin signaling, but recombinant alpha N-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of alpha N-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.
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