학술논문
Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration.
Document Type
article
Author
Schaffer, Ashleigh E; Breuss, Martin W; Caglayan, Ahmet Okay; Al-Sanaa, Nouriya; Al-Abdulwahed, Hind Y; Kaymakçalan, Hande; Yılmaz, Cahide; Zaki, Maha S; Rosti, Rasim O; Copeland, Brett; Baek, Seung Tae; Musaev, Damir; Scott, Eric C; Ben-Omran, Tawfeg; Kariminejad, Ariana; Kayserili, Hulya; Mojahedi, Faezeh; Kara, Majdi; Cai, Na; Silhavy, Jennifer L; Elsharif, Seham; Fenercioglu, Elif; Barshop, Bruce A; Kara, Bulent; Wang, Rengang; Stanley, Valentina; James, Kiely N; Nachnani, Rahul; Kalur, Aneesha; Megahed, Hisham; Incecik, Faruk; Danda, Sumita; Alanay, Yasemin; Faqeih, Eissa; Melikishvili, Gia; Mansour, Lobna; Miller, Ian; Sukhudyan, Biayna; Chelly, Jamel; Dobyns, William B; Bilguvar, Kaya; Jamra, Rami Abou; Gunel, Murat; Gleeson, Joseph G
Source
Nature genetics. 50(8)
Subject
Language
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.