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

Neuronal migrationdefects, 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- cateninparalog, αE- catenin, acts as a switch regulating the balance between β- cateninand Arp2/3 actin filament activities1. Loss of αN- catenindid not affect β- cateninsignaling, but recombinant αN- catenininteracted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of αN- cateninor 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 cateninfamily member with biallelic mutations in humans, causing a new pachygyriasyndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.