Browsing by Author "Caglayan, Ahmet Okay"

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Biallelic loss of human CTNNA2, encoding alpha N-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration
(NATURE PUBLISHING GROUP, 2018-01-01) Schaffer, Ashleigh E.; Breuss, Martin W.; Caglayan, Ahmet Okay; Al-Sanaa, Nouriya; Al-Abdulwahed, Hind Y.; Kaymakcalan, 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; Abou Jamra, Rami; Gunel, Murat; Gleeson, Joseph G.
Neuronal 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.
Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO
(AMER ASSOC ADVANCEMENT SCIENCE, 2013-01-01) Clark, Victoria E.; Erson-Omay, E. Zeynep; Serin, Akdes; Yin, Jun; Cotney, Justin; Oezduman, Koray; Avsar, Timuin; Li, Jie; Murray, Phillip B.; Henegariu, Octavian; Yilmaz, Saliha; Guenel, Jennifer Moliterno; Carrion-Grant, Geneive; Yilmaz, Baran; Grady, Conor; Tanrikulu, Bahattin; Bakircioglu, Mehmet; Kaymakcalan, Hande; Caglayan, Ahmet Okay; Sencar, Leman; Ceyhun, Emre; Atik, A. Fatih; Bayri, Yasar; Bai, Hanwen; Kolb, Luis E.; Hebert, Ryan M.; Omay, S. Bulent; Mishra-Gorur, Ketu; Choi, Murim; Overton, John D.; Holland, Eric C.; Mane, Shrikant; State, Matthew W.; Bilguevar, Kaya; Baehring, Joachim M.; Gutin, Philip H.; Piepmeier, Joseph M.; Vortmeyer, Alexander; Brennan, Cameron W.; Pamir, M. Necmettin; Kilic, Tuerker; Lifton, Richard P.; Noonan, James P.; Yasuno, Katsuhito; Guenel, Murat
We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation ( K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in similar to 5\% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.
Recessive LAMC3 mutations cause malformations of occipital cortical development
(NATURE PUBLISHING GROUP, 2011-01-01) Barak, Tanyeri; Kwan, Kenneth Y.; Louvi, Angeliki; Demirbilek, Veysi; Saygi, Serap; Tuysuz, Beyhan; Choi, Murim; Boyaci, Huseyin; Doerschner, Katja; Zhu, Ying; Kaymakcalan, Hande; Yilmaz, Saliha; Bakircioglu, Mehmet; Caglayan, Ahmet Okay; Oeztuerk, Ali Kemal; Yasuno, Katsuhito; Brunken, William J.; Atalar, Ergin; Yalcinkaya, Cengiz; Dincer, Alp; Bronen, Richard A.; Mane, Shrikant; Ozcelik, Tayfun; Lifton, Richard P.; Sestan, Nenad; Bilguevar, Kaya; Guenel, Murat
The biological basis for regional and inter-species differences in cerebral cortical morphology is poorly understood. We focused on consanguineous Turkish families with a single affected member with complex bilateral occipital cortical gyration abnormalities. By using whole-exome sequencing, we initially identified a homozygous 2-bp deletion in LAMC3, the laminin. 3 gene, leading to an immediate premature termination codon. In two other affected individuals with nearly identical phenotypes, we identified a homozygous nonsense mutation and a compound heterozygous mutation. In human but not mouse fetal brain, LAMC3 is enriched in postmitotic cortical plate neurons, localizing primarily to the somatodendritic compartment. LAMC3 expression peaks between late gestation and late infancy, paralleling the expression of molecules that are important in dendritogenesis and synapse formation. The discovery of the molecular basis of this unusual occipital malformation furthers our understanding of the complex biology underlying the formation of cortical gyrations.
Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis
(OXFORD UNIV PRESS INC, 2015-01-01) Erson-Omay, E. Zeynep; Caglayan, Ahmet Okay; Schultz, Nikolaus; Weinhold, Nils; Omay, S. Bulent; Ozduman, Koray; Koksal, Yavuz; Li, Jie; Harmanci, Akdes Serin; Clark, Victoria; Carrion-Grant, Geneive; Baranoski, Jacob; Caglar, Caner; Barak, Tanyeri; Coskun, Suleyman; Baran, Burcin; Kose, Dogan; Sun, Jia; Bakircioglu, Mehmet; Gunel, Jennifer Moliterno; Pamir, M. Necmettin; Mishra-Gorur, Ketu; Bilguvar, Kaya; Yasuno, Katsuhito; Vortmeyer, Alexander; Huttner, Anita J.; Sander, Chris; Gunel, Murat
Background. Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. Methods. We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. Results. We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these ``ultramutated{''} tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. Conclusions. We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.
Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations
(NATURE PUBLISHING GROUP, 2010-01-01) Bilguvar, Kaya; Ozturk, Ali Kemal; Louvi, Angeliki; Kwan, Kenneth Y.; Choi, Murim; Tatli, Burak; Yalnizoglu, Dilek; Tuysuz, Beyhan; Caglayan, Ahmet Okay; Gokben, Sarenur; Kaymakcalan, Hande; Barak, Tanyeri; Bakircioglu, Mehmet; Yasuno, Katsuhito; Ho, Winson; Sanders, Stephan; Zhu, Ying; Yilmaz, Sanem; Dincer, Alp; Johnson, Michele H.; Bronen, Richard A.; Kocer, Naci; Per, Hueseyin; Mane, Shrikant; Pamir, Mehmet Necmettin; Yalcinkaya, Cengiz; Kumandas, Sefer; Topcu, Meral; Ozmen, Meral; Sestan, Nenad; Lifton, Richard P.; State, Matthew W.; Gunel, Murat
The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers(1,2). An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development(3-6). Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.