Journal Article

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

Baek, Seung Tae, Nachnani, Rahul, Barshop, Bruce A., Breuss, Martin W., Fenercioglu, Elif, Sukhudyan, Biayna, Silhavy, Jennifer L., Elsharif, Seham, Caglayan, Ahmet Okay, Rosti, Rasim O., Kariminejad, Ariana, James, Kiely N., Cai, Na, Ben-Omran, Tawfeg, Dobyns, William B., Al-Sanaa, Nouriya, Kara, Bulent, Miller, Ian, Schaffer, Ashleigh E., Melikishvili, Gia, Incecik, Faruk, Kaymakçalan, Hande, Al-Abdulwahed, Hind Y., Copeland, Brett, Kalur, Aneesha, Scott, Eric C., Alanay, Yasemin, Mansour, Lobna, Danda, Sumita, Wang, Rengang, Megahed, Hisham, Musaev, Damir, Kara, Majdi, Yılmaz, Cahide, Chelly, Jamel, Jamra, Rami Abou, Bilguvar, Kaya, Mojahedi, Faezeh, Stanley, Valentina, Kayserili, Hulya, Gunel, Murat, Faqeih, Eissa, Gleeson, Joseph G., Zaki, Maha S.

2018

Overview

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 activities 1 . 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. Biallelic truncating mutations in CTNNA2 , encoding αN-catenin, cause a new pachygyria syndrome associated with actin regulation and ARP2 and ARP3 repression in neurons.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/1 / 13/100 / 13/106 / 13/44 / 14/63 / 38/91 / 45/23 / 45/41 / 59/57 / 692/699 / 692/699/375 / Actin / Actin-Related Protein 2-3 Complex - genetics / Actin-Related Protein 2-3 Complex - metabolism / Agriculture / alpha Catenin - genetics / alpha Catenin - metabolism / Animal Genetics and Genomics / Animals / Biomedical and Life Sciences / Biomedicine / Brain / Cancer Research / Catenin / Cell migration / Cell Movement - genetics / Cerebral cortex / Cerebral Cortex - metabolism / Cerebral Cortex - pathology / Cerebral Cortex - physiology / Coding / Cytoskeleton / Defects / Embryo, Mammalian / Gene Function / Genome, Human / Genomes / Human Genetics / Humans / Letter / Mice / Mice, Inbred C57BL / Mutation / Nerve Tissue Proteins - genetics / Neurons / Neurons - metabolism / Neurons - pathology / NMR / Nuclear magnetic resonance / Pedigree / Phenotypes / Proteins / Regulation / Stem cells