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dc.contributor.authorSchaffer, Ashleigh E.
dc.contributor.authorBreuss, Martin W.
dc.contributor.authorCaglayan, Ahmet Okay
dc.contributor.authorAl-Sanaa, Nouriya
dc.contributor.authorAl-Abdulwahed, Hind Y.
dc.contributor.authorKaymakcalan, Hande
dc.contributor.authorGleeson, Joseph G.
dc.date.accessioned2019-08-13T12:10:23Z
dc.date.accessioned2019-08-13T15:55:46Z
dc.date.available2019-08-13T12:10:23Z
dc.date.available2019-08-13T15:55:46Z
dc.date.issued2018
dc.identifier.issn1061-4036
dc.identifier.issn1546-1718
dc.identifier.urihttps://dx.doi.org/10.1038/s41588-018-0166-0
dc.identifier.urihttp://hdl.handle.net/11446/2122
dc.descriptionWOS: 000440423400008en_US
dc.descriptionPubMed ID: 30013181en_US
dc.description.abstractNeuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding alpha N-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 alpha N-catenin paralog, alpha E-catenin, acts as a switch regulating the balance between beta-catenin and Arp2/3 actin filament activities(1). Loss of alpha N-catenin did not affect beta-catenin signaling, but recombinant alpha N-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of alpha N-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.en_US
dc.description.sponsorshipNIH [R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101]; Qatar National Research Fund [6-1463-351]; Simons Foundation Autism Research Initiative; Howard Hughes Medical Institute; A.P. Giannini Fellowship; NIH Pathway to Independence Award [R00HD082337]; 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation; Yale Center for Mendelian Disorders [UMIHG008900, UMIHG006504]en_US
dc.description.sponsorshipWe thank the patients and their families for participation. We thank A. Wynshaw-Boris for generous scientific and editorial input. The research was supported by NIH R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101, Qatar National Research Fund number 6-1463-351, the Simons Foundation Autism Research Initiative, and the Howard Hughes Medical Institute (to J.G.G). A.E.S. is a recipient of an A.P. Giannini Fellowship and an NIH Pathway to Independence Award, R00HD082337. S.T.B. is supported by a 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. We thank the Broad Institute and Yale Center for Mendelian Disorders (UMIHG008900 to D. MacArthur and H. Rehm, and UMIHG006504 to R. Lifton and M.G.), and the Gregory M. Kiez and Mehmet Kutman Foundation (to M.G). We acknowledge M. Gerstein, S. Mane, A. B. Ekici, and S. Uebe for sequencing support and analysis, the Yale Biomedical High Performance Computing Center for data analysis and storage, the Yale Program on Neurogenetics, and the Yale Center for Human Genetics and Genomics. Exome data have been deposited into the database of Genotypes and Phenotypes (phs000288).en_US
dc.language.isoengen_US
dc.publisherNATURE PUBLISHING GROUPen_US
dc.relation.isversionof10.1038/s41588-018-0166-0en_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleBiallelic loss of human CTNNA2, encoding alpha N-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migrationen_US
dc.typearticleen_US
dc.relation.journalNATURE GENETICSen_US
dc.contributor.departmentDBÜen_US
dc.identifier.issue8en_US
dc.identifier.volume50en_US
dc.identifier.startpage1093en_US
dc.identifier.endpage+en_US
dc.contributor.authorID0000-0002-1542-1399en_US
dc.contributor.authorID0000-0002-1164-697Xen_US
dc.contributor.authorID0000-0001-7840-0002en_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US


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