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Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration.
Schaffer, Ashleigh E; Breuss, Martin W; Caglayan, Ahmet Okay; Al-Sanaa, Nouriya; Al-Abdulwahed, Hind Y; Kaymakçalan, Hande; Yilmaz, 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.
Afiliación
  • Schaffer AE; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA. ashleigh.schaffer@case.edu.
  • Breuss MW; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA. ashleigh.schaffer@case.edu.
  • Caglayan AO; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Al-Sanaa N; Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT, USA.
  • Al-Abdulwahed HY; Department of Medical Genetics, Istanbul Bilim University, Istanbul, Turkey.
  • Kaymakçalan H; Department of Pediatrics, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.
  • Yilmaz C; Department of Pediatrics, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.
  • Zaki MS; Department of Pediatrics, Istanbul Bilim University, Istanbul, Turkey.
  • Rosti RO; Department of Pediatrics, Yildirim Beyazit University, Ankara, Turkey.
  • Copeland B; Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
  • Baek ST; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Musaev D; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Scott EC; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Ben-Omran T; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Kariminejad A; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Kayserili H; Clinical and Metabolic Genetics Section, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
  • Mojahedi F; Kariminejad-Najmabadi Pathology and Genetic Center, Tehran, Iran.
  • Kara M; Department of Medical Genetics, Koç University School of Medicine, Istanbul, Turkey.
  • Cai N; Mashhad Medical Genetic Counseling Center, Mashhad, Iran.
  • Silhavy JL; University of Tripoli, Tripoli Children's Hospital, Tripoli, Libya.
  • Elsharif S; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Fenercioglu E; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Barshop BA; University of Tripoli, Tripoli Children's Hospital, Tripoli, Libya.
  • Kara B; L.E.S. Mikrogen Genetic Diseases Diagnosis Center, Istanbul, Turkey.
  • Wang R; Department of Pediatrics, Biochemical Genetics Program, University of California, San Diego, San Diego, CA, USA.
  • Stanley V; Department of Pediatric Neurology, Kocaeli University, Kocaeli, Turkey.
  • James KN; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Nachnani R; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Kalur A; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Megahed H; Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
  • Incecik F; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
  • Danda S; Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
  • Alanay Y; Department of Pediatric Neurology, Cukurova University, Adana, Turkey.
  • Faqeih E; Department of Clinical Genetics, Christian Medical College and Hospital, Vellore, India.
  • Melikishvili G; Pediatric Genetics Unit, Department of Pediatrics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.
  • Mansour L; Section of Medical Genetics, Department of Pediatrics, King Fahad Medical City, Children's Hospital, Riyadh, Saudi Arabia.
  • Miller I; Department of Pediatrics, MediClubGeorgia, Tbilisi, Georgia.
  • Sukhudyan B; Pediatric Department, Neuropediatric Unit, Cairo University Children's Hospital, Cairo, Egypt.
  • Chelly J; Neurology Department, Nicklaus Children's Hospital, Miami, FL, USA.
  • Dobyns WB; Arabkir Joint Medical Center and Institute of Child and Adolescent Health, Yerevan, Armenia.
  • Bilguvar K; Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France.
  • Jamra RA; Departments of Pediatrics and Neurology, University of Washington, Seattle, WA, USA.
  • Gunel M; Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT, USA.
  • Gleeson JG; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
Nat Genet ; 50(8): 1093-1101, 2018 08.
Article en En | MEDLINE | ID: mdl-30013181
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 ß-catenin and Arp2/3 actin filament activities1. Loss of αN-catenin did not affect ß-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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Movimiento Celular / Corteza Cerebral / Complejo 2-3 Proteico Relacionado con la Actina / Alfa Catenina / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2018 Tipo del documento: Article
Texto completo
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Movimiento Celular / Corteza Cerebral / Complejo 2-3 Proteico Relacionado con la Actina / Alfa Catenina / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Año: 2018 Tipo del documento: Article