Details

Autor(en) / Beteiligte

• 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.

Titel

Bi-allelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 over-activity and disordered cortical neuronal migration

Ist Teil von

• Nature genetics, 2018-07, Vol.50 (8), p.1093-1101

Erscheinungsjahr

2018

Beschreibungen/Notizen

• Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here we identify bi-allelic 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 α-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 (ABD) 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 bi-allelic mutations in human, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons.