Person: ÇAĞLAR, CANER
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Publication Metadata only Restriction of food intake by PPP1R17-expressing neurons in the DMH(2021-03-01T00:00:00Z) Caglar, CANER; Friedman, Jeffrey; ÇAĞLAR, CANERLeptin-deficient ob/ob mice eat voraciously, and their food intake is markedly reduced by leptin treatment. In order to identify potentially novel sites of leptin action, we used PhosphoTRAP to molecularly profile leptin-responsive neurons in the hypothalamus and brainstem. In addition to identifying several known leptin responsive populations, we found that neurons in the dorsomedial hypothalamus (DMH) of ob/ob mice expressing protein phosphatase 1 regulatory subunit 17 (PPP1R17) constitutively express cFos and that this is suppressed by leptin treatment. Because ob mice are hyperphagic, we hypothesized that activating PPP1R17 neurons would increase food intake. However, chemogenetic activation of PPP1R17 neurons decreased food intake and body weight of ob/ob mice while inhibition of PPP1R17 neurons increased them. Similarly, in a scheduled feeding protocol that elicits increased consumption, mice also ate more when PPP1R17 neurons were inhibited and ate less when they were activated. Finally, we found that pair-feeding of ob mice reduced cFos expression to a similar extent as leptin and that reducing the amount of food available during scheduled feeding in DMHPpp1r17 neurons also decreased cFos in DMHPpp1r17 neurons. Finally, these neurons do not express the leptin receptor, suggesting that the effect of leptin on these neurons is indirect and secondary to reduced food intake. In aggregate, these results show that PPP1R17 neurons in the DMH are activated by increased food intake and in turn restrict intake to limit overconsumption, suggesting that they function to constrain binges of eating.Publication Metadata only Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors(2014-12-01T00:00:00Z) Mishra-Gorur, Ketu; Caglayan, Ahmet Okay; Schaffer, Ashleigh E.; Chabu, Chiswili; Henegariu, Octavian; Vonhoff, Fernando; Akguemues, Goezde Tugce; Nishimura, Sayoko; Han, Wenqi; Tu, Shu; Baran, Burcin; Gumus, Hakan; Dilber, Cengiz; Zaki, Maha S.; Hossni, Heba A. A.; Riviere, Jean-Baptiste; Kayserili, Huelya; Spencer, Emily G.; Rosti, Rasim Oe; Schroth, Jana; Per, Huseyin; Caglar, CANER; Caglar, Cagri; Doelen, Duygu; Baranoski, Jacob F.; Kumandas, Sefer; Minja, Frank J.; Erson-Omay, E. Zeynep; Mane, Shrikant M.; Lifton, Richard P.; Xu, Tian; Keshishian, Haig; Dobyns, William B.; Chi, Neil C.; Sestan, Nenad; Louvi, Angeliki; Bilguevar, Kaya; Yasuno, Katsuhito; Gleeson, Joseph G.; Guenel, Murat; ÇAĞLAR, CANERExome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development.Publication Metadata only Longitudinal analysis of treatment-induced genomic alterations in gliomas(2017-02-01T00:00:00Z) Erson-Omay, E. Zeynep; Henegariu, Octavian; Omay, S. Bulent; Harmanci, Akdes Serin; Youngblood, Mark W.; Mishra-Gorur, Ketu; Li, Jie; ÖZDUMAN, Koray; Carrion-Grant, Geneive; Clark, Victoria E.; Caglar, CANER; Bakircioglu, Mehmet; Pamir, M. Necmettin; Tabar, Viviane; Vortmeyer, Alexander O.; Bilguvar, Kaya; Yasuno, Katsuhito; DeAngelis, Lisa M.; Baehring, Joachim M.; Moliterno, Jennifer; Gunel, Murat; ÇAĞLAR, CANERBackground: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy; however, individual tumors display immense variability in their response to these approaches. Genomic techniques such as whole-exome sequencing (WES) provide an opportunity to understand the molecular basis of this variability.Publication Metadata only CLP1 Founder Mutation Links tRNA Splicing and Maturation to Cerebellar Development and Neurodegeneration(2014-04-01T00:00:00Z) Schaffer, Ashleigh E.; Eggens, Veerle R. C.; Caglayan, Ahmet Okay; Reuter, Miriam S.; Scott, Eric; Coufal, Nicole G.; Silhavy, Jennifer L.; Xue, Yuanchao; Kayserili, Hulya; Yasuno, Katsuhito; Rosti, Rasim Ozgur; Abdellateef, Mostafa; Caglar, CANER; Kasher, Paul R.; Cazemier, J. Leonie; Weterman, Marian A.; Cantagrel, Vincent; Cai, Na; Zweier, Christiane; Altunoglu, Umut; Satkin, N. Bilge; Aktar, Fesih; Tuysuz, Beyhan; Yalcinkaya, Cengiz; Caksen, Huseyin; Bilguvar, Kaya; Fu, Xiang-Dong; Trotta, Christopher R.; Gabriel, Stacey; Reis, Andre; Gunel, Murat; Baas, Frank; Gleeson, Joseph G.; ÇAĞLAR, CANERNeurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans.Publication Metadata only Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis(2015-10-01T00:00:00Z) Erson-Omay, E. Zeynep; Caglayan, Ahmet Okay; Schultz, Nikolaus; Weinhold, Nils; Omay, S. Bulent; ÖZDUMAN, 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; ÇAĞLAR, CANERBackground. 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.Publication Metadata only NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy(2015-01-01T00:00:00Z) Caglayan, Ahmet Okay; Comu, Sinan; Baranoski, Jacob F.; Parman, Yesim; Kaymakcalan, Hande; Akgumus, Gozde Tugce; Caglar, CANER; Dolen, Duygu; Erson-Omay, Emine Zeynep; Harmanci, Akdes Serin; Mishra-Gorur, Ketu; Freeze, Hudson H.; Yasuno, Katsuhito; Bilguvar, Kaya; Gunel, Murat; ÇAĞLAR, CANERN-glycanase 1 (NGLY1) is a conserved enzyme that is responsible for the deglycosylation of misfolded N-glycosylated proteins in the cytoplasm prior to their proteasome-mediated degradation. Disruption of this degradation process has been associated with various neurologic diseases including amyotrophic lateral sclerosis and Parkinson-s disease. Here, we describe two siblings with neuromotor impairment, apparent intellectual disability, corneal opacities, and neuropathy who were found to possess a novel homozygous frame-shift mutation due to a 4 base pair deletion in NGLY1 (c.1533_1536delTCAA. p.Asn511LysfsX51). We hypothesize that this mutation likely limits the capability of neuronal cells to respond to stress due to accumulation of misfolded proteins, thereby impairing their survival and resulting in progressive loss of neurological function. (C) 2014 Elsevier Masson SAS. All rights reserved.Publication Metadata only Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly(2016-11-01T00:00:00Z) Jerber, Julie; Zaki, Maha S.; Al-Aama, Jumana Y.; Rosti, Rasim Ozgur; Ben-Omran, Tawfeg; Dikoglu, Esra; Silhavy, Jennifer L.; Caglar, CANER; Musaev, Damir; Albrecht, Beate; Campbell, Kevin P.; Willer, Tobias; Almuriekhi, Mariam; Caglayan, Ahmet Okay; Vajsar, Jiri; Bilguvar, Kaya; Ogur, Gonul; Abou Jamra, Rami; Gunel, Murat; Gleeson, Joseph G.; ÇAĞLAR, CANERCobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha-dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement.Publication Metadata only Brain Malformations Associated With Knobloch Syndrome-Review of Literature, Expanding Clinical Spectrum, and Identification of Novel Mutations(2014-12-01T00:00:00Z) Caglayan, Ahmet Okay; Baranoski, Jacob E.; Aktar, Fesih; Han, Wengi; Tuysuz, Beyhan; Guzel, Asian; Guclu, Bulent; Kaymakcalan, Hande; Aktekin, Berrin; Akgumus, Gozde Tugce; Murray, Phillip B.; Erson-Omay, Emine Z.; Caglar, CANER; Bakircioglu, Mehmet; Sakalar, Yildirim Bayezit; Guzel, Ebru; Demir, Nihat; Tuncer, Oguz; Senturk, Senem; Ekici, Saris; Minja, Frank J.; Sestan, Nenad; Yasuno, Katsuhito; Bilguvar, Kaya; Caksen, Huseyin; Gunel, Murat; ÇAĞLAR, CANERBACKGROUND: Knobloch syndrome is a rare, autosomal recessive, developmental disorder characterized by stereotyped ocular abnormalities with or without occipital skull deformities (encephalocele, bone defects, and cutis aplasia). Although there is clear heterogeneity in clinical presentation, central nervous system malformations, aside from the characteristic encephalocele, have not typically been considered a component of the disease phenotype. METHODS: Four patients originally presented for genetic evaluation of symptomatic structural brain malformations. Whole-genome genotyping, whole-exome sequencing, and confirmatory Sanger sequencing were performed. Using immunohistochemical analysis, we investigated the protein expression pattern of COL18A1 in the mid-fetal and adult human cerebral cortex and then analyzed the spatial and temporal changes in the expression pattern of COL18A1 during human cortical development using the Human Brain Transcriptome database. RESULTS: We identified two novel homozygous deleterious frame-shift mutations in the COL18A1 gene. On further investigation of these patients and their families, we found that many exhibited certain characteristics of Knobloch syndrome, including pronounced ocular defects. Our data strongly support an important role for COL18A1 in brain development, and this report contributes to an enhanced characterization of the brain malformations that can result from deficiencies of collagen XVIII. CONCLUSIONS: This case series highlights the diagnostic power and clinical utility of whole-exome sequencing technology allowing clinicians and physician scientists to better understand the pathophysiology and presentations of rare diseases. We suggest that patients who are clinically diagnosed with Knobloch syndrome and/or found to have COL18A1. mutations via genetic screening should be investigated for potential structural brain abnormalities even in the absence of an encephalocele.Publication Metadata only A NEW PATIENT WITH ANDERMANN SYNDROME: AN UNDERDIAGNOSED CLINICAL GENETICS ENTITY?(2013-01-01T00:00:00Z) Degerliyurt, A.; Akgumus, G.; Caglar, CANER; Bilguvar, K.; Caglayan, A. O.; ÇAĞLAR, CANERA new patient with Andermann syndrome: an underdiagnosed clinical genetics entity?: Andermann syndrome is an autosomal recessive disorder characterized by the agenesis of the corpus callosum and peripheral neuropathy (ACCPN). People affected by Andermann syndrome have mental retardation, areflexia and severe progressive neuropathy often accompanied by psychiatric symptoms, and they typically die in the third decade of their life. We here report the case of a 5 year-old Turkish boy born to consanguineous parents. He presented to clinical attention with delayed development and epilepsy and was found to have dysmorphic characteristics, areflexia and severe neuropathy on exam. Imaging studies were remarkable for agenesis of corpus callosum. SLC12A6 screening revealed the presence of R1011X mutation; potentially responsible for the changes in intracellular and extracellular ion concentrations, leading to defects in cortical electrical activity.Publication Metadata only Functional analysis reveals differential effects of glutamate and MCH neuropeptide in MCH neurons(2018-07-01T00:00:00Z) Schneeberger, Marc; Tan, Keith; Nectow, Alexander R.; Parolari, Luca; Caglar, CANER; Azevedo, Estefania; Li, Zhiying; Domingos, Ana; Friedman, Jeffrey M.; ÇAĞLAR, CANERObjectives: Melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) regulate food intake and body weight, glucose metabolism and convey the reward value of sucrose. In this report, we set out to establish the respective roles of MCH and conventional neurotransmitters in these neurons.