Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration.
SCIE
SCOPUS
- Title
- Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration.
- Authors
- Seung Tae Baek; Ashleigh E. Schaffer; Martin W. Breuss; Ahmet Okay Caglayan; Nouriya Al-Sanaa; Hind Y. Al-Abdulwahed; Hande Kaymakçalan; Cahide Yılmaz; Maha S. Zaki; Rasim O. Rosti; Brett Copeland; Damir Musaev; Eric C. Scott; Tawfeg Ben-Omran; Ariana Kariminejad; Hulya Kayserili; Faezeh Mojahedi; Majdi Kara; Na Cai; Jennifer L. Silhavy; Seham Elsharif; Elif Fenercioglu; Bruce A. Barshop; Bulent Kara; Rengang Wang; Valentina Stanley; Kiely N. James; Rahul Nachnani; Aneesha Kalur; Hisham Megahed; Faruk Incecik; Sumita Danda; Yasemin Alanay; Eissa Faqeih; Gia Melikishvili; Lobna Mansour; Ian Miller; Biayna Sukhudyan; Jamel Chelly; William B. Dobyns; Kaya Bilguvar; Rami Abou Jamra; Murat Gunel; Joseph G. Gleeson
- Date Issued
- 2018-08
- Publisher
- NATURE PUBLISHING GROUP
- Abstract
- Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding αN-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 αN-catenin paralog, αE-catenin, acts as a switch regulating the balance between β-catenin and Arp2/3 actin filament activities1. Loss of αN-catenin did not affect β-catenin signaling, but recombinant αN-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN-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.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/94282
- DOI
- 10.1038/s41588-018-0166-0
- ISSN
- 1061-4036
- Article Type
- Article
- Citation
- NATURE GENETICS, vol. 50, no. 8, page. 1093 - 1101, 2018-08
- Files in This Item:
- There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.