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Nat Genet. 2018 Aug;50(8):1093-1101. doi: 10.1038/s41588-018-0166-0. Epub 2018 Jul 16.

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

Author information

1
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.
2
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA. ashleigh.schaffer@case.edu.
3
Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA.
4
Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT, USA.
5
Department of Medical Genetics, Istanbul Bilim University, Istanbul, Turkey.
6
Department of Pediatrics, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.
7
Department of Pediatrics, Istanbul Bilim University, Istanbul, Turkey.
8
Department of Pediatrics, Yıldırım Beyazıt University, Ankara, Turkey.
9
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
10
Clinical and Metabolic Genetics Section, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
11
Kariminejad-Najmabadi Pathology and Genetic Center, Tehran, Iran.
12
Department of Medical Genetics, Koç University School of Medicine, Istanbul, Turkey.
13
Mashhad Medical Genetic Counseling Center, Mashhad, Iran.
14
University of Tripoli, Tripoli Children's Hospital, Tripoli, Libya.
15
L.E.S. Mikrogen Genetic Diseases Diagnosis Center, Istanbul, Turkey.
16
Department of Pediatrics, Biochemical Genetics Program, University of California, San Diego, San Diego, CA, USA.
17
Department of Pediatric Neurology, Kocaeli University, Kocaeli, Turkey.
18
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
19
Department of Pediatric Neurology, Cukurova University, Adana, Turkey.
20
Department of Clinical Genetics, Christian Medical College and Hospital, Vellore, India.
21
Pediatric Genetics Unit, Department of Pediatrics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.
22
Section of Medical Genetics, Department of Pediatrics, King Fahad Medical City, Children's Hospital, Riyadh, Saudi Arabia.
23
Department of Pediatrics, MediClubGeorgia, Tbilisi, Georgia.
24
Pediatric Department, Neuropediatric Unit, Cairo University Children's Hospital, Cairo, Egypt.
25
Neurology Department, Nicklaus Children's Hospital, Miami, FL, USA.
26
Arabkir Joint Medical Center and Institute of Child and Adolescent Health, Yerevan, Armenia.
27
Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France.
28
Departments of Pediatrics and Neurology, University of Washington, Seattle, WA, USA.
29
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
30
Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, USA. jogleeson@ucsd.edu.

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.

PMID:
30013181
PMCID:
PMC6072555
DOI:
10.1038/s41588-018-0166-0
[Indexed for MEDLINE]
Free PMC Article

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