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4. A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR

Author

White, H, Deprez, L, Corbisier, P, Hall, V, Lin, F, Mazoua, S, Trapmann, S, Aggerholm, A, Andrikovics, H, Akiki, S, Barbany, G, Boeckx, N, Bench, A, Catherwood, M, Cayuela, J-M, Chudleigh, S, Clench, T, Colomer, D, Daraio, F, Dulucq, S, Farrugia, J, Fletcher, L, Foroni, L, Ganderton, R, Gerrard, G, Gineikiene, E, Hayette, S, El Housni, H, Izzo, B, Jansson, M, Johnels, P, Jurcek, T, Kairisto, V, Kizilors, A, Kim, D-W, Lange, T, Lion, T, Polakova, K M, Martinelli, G, McCarron, S, Merle, P A, Milner, B, Mitterbauer-Hohendanner, G, Nagar, M, Nickless, G, Nomdedéu, J, Nymoen, D A, Leibundgut, E O, Ozbek, U, Pajic, T, Pfeifer, H, Preudhomme, C, Raudsepp, K, Romeo, G, Sacha, T, Talmaci, R, Touloumenidou, T, Van der Velden, V HJ, Waits, P, Wang, L, Wilkinson, E, Wilson, G, Wren, D, Zadro, R, Ziermann, J, Zoi, K, Müller, M C, Hochhaus, A, Schimmel, H, Cross, N CP, and Emons, H

Published
2015
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8. Biallelic NALCN variant detected by homozygosity mapping and whole exome sequencing in a consanguineous family from Turkey

Author

Susgun, S., Yucesan, E., Kocaturk, O., Calik, M., Ozbek, U., Iseri, S. Ugur, and SÜSGÜN, Seda

Subjects
Süsgün S., Yücesan E., Kocatürk Ö., Çalık M., Özbek U., Uğur İşeri S. A. , -Biallelic NALCN variant detected by homozygosity mapping and whole exome sequencing in a consanguineous family from Turkey-, European Human Genetics Virtual Conference (ESHG 2020.2), Berlin, Almanya, 6 - 09 Haziran 2020
Abstract

Bezmiâlem Vakıf Üniversitesi Türkiye Bilimsel Ve Teknolojik Araştırma Kurumu ( Tubitak )

Published
2020

21. Identification of the post-zygotic mosaic nonsense mutation in WDR45gene leading to beta-propeller protein-associated neurodegeneration and defining sex chromosomal mosaicism at whole exome sequencing

Author

Nihan Hande Akcakaya, Salman, B., Arguden, Y. Tarkan, Gormez, Z., Donmez, R., Colakoglu, B., Yapici, Z., Hacihanefioglu, S., Ozbek, U., Iseri, S. A. Ugur, İstinye Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Yazılım Mühendisliği Bölümü, and Gormez, Zeliha

Abstract

Gormez, Zeliha (isu author) 51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG) -- JUN 16-19, 2018 -- Milan, ITALY … European Soc Human Genet Scientific Research Projects Coordination Unit of Istanbul UniversityIstanbul University [26646] This work was supported by grants from the Scientific Research Projects Coordination Unit of Istanbul University, Project Number 26646. WOS:000489313104216 Q2

Published
2019

22. No evidence for a BRD2 promoter hypermethylation inblood leukocytes of Europeans with juvenile myoclonic epilepsy

Author

Schulz, H, Ruppert, A-K, Zara, F, Madia, F, Iacomino, M, Vari, MS, Balagura, G, Minetti, C, Striano, P, Blanche, A, Marini, C, Guerrini, R, Weber, YG, Becker, F, Lerche, H, Kapser, C, Schankin, CJ, Kunz, WS, Moller, RS, Oliver, KL, Bellows, ST, Mullen, SA, Berkovic, SF, Scheffer, IE, Caglayan, H, Ozbek, U, Hoffmann, P, Schramm, S, Tsortouktzidis, D, Becker, AJ, Sander, T, Schulz, H, Ruppert, A-K, Zara, F, Madia, F, Iacomino, M, Vari, MS, Balagura, G, Minetti, C, Striano, P, Blanche, A, Marini, C, Guerrini, R, Weber, YG, Becker, F, Lerche, H, Kapser, C, Schankin, CJ, Kunz, WS, Moller, RS, Oliver, KL, Bellows, ST, Mullen, SA, Berkovic, SF, Scheffer, IE, Caglayan, H, Ozbek, U, Hoffmann, P, Schramm, S, Tsortouktzidis, D, Becker, AJ, and Sander, T

Abstract

Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain-containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives. In contrast, we found a uniform low average percentage of methylation (<4.5%) for 13 CpG76-CpGs in whole blood cells from 782 unrelated European Caucasians, including 116 JME patients, 196 patients with genetic absence epilepsies, and 470 control subjects. We also failed to confirm an allelic association of the BRD2 promoter single nucleotide polymorphism (SNP) rs3918149 with JME (Armitage trend test, P = 0.98), and we did not detect a substantial impact of SNP rs3918149 on CpG76 methylation in either 116 JME patients (methylation quantitative trait loci [meQTL], P = 0.29) or 470 German control subjects (meQTL, P = 0.55). Our results do not support the previous observation that a high DNA methylation level of the BRD2 promoter CpG76 island is a prevalent epigenetic motif associated with JME in Caucasians.

Published
2019

26. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Author

EPICURE Consortium, Leu C., de Kovel C. G., Zara F., Striano P., Pezzella M., Robbiano A., Bianchi A., Coppola A., Giallonardo A. T., Beccaria F., Trenité D. K., Lindhout D., Gaus V., Schmitz B., Janz D., Weber Y. G., Becker F., Lerche H., Kleefuss Lie A. A., Hallman K., Kunz W. S., Elger C. E., Muhle H., Stephani U., Møller R. S., Hjalgrim H., Mullen S., Scheffer I. E., Berkovic S. F., Everett K. V., Gardiner M. R., Marini C., Guerrini R., Lehesjoki A. E., Siren A., Nabbout R., Baulac S., Leguern E., Serratosa J. M., Rosenow F., Feucht M., Unterberger I., Covanis A., Suls A., Weckhuysen S., Kaneva R., Caglayan H., Turkdogan D., Baykan B., Bebek N., Ozbek U., Hempelmann A., Schulz H., Rüschendorf F., Trucks H., Nürnberg P., Avanzini G., Koeleman B. P., Sander T., BISULLI, FRANCESCA, TINUPER, PAOLO, YÜCESAN, EMRAH, EPICURE Consortium, Leu C., de Kovel C.G., Zara F., Striano P., Pezzella M., Robbiano A., Bianchi A., Bisulli F., Coppola A., Giallonardo A.T., Beccaria F., Trenité D.K., Lindhout D., Gaus V., Schmitz B., Janz D., Weber Y.G., Becker F., Lerche H., Kleefuss-Lie A.A., Hallman K., Kunz W.S., Elger C.E., Muhle H., Stephani U., Møller R.S., Hjalgrim H., Mullen S., Scheffer I.E., Berkovic S.F., Everett K.V., Gardiner M.R., Marini C., Guerrini R., Lehesjoki A.E., Siren A., Nabbout R., Baulac S., Leguern E., Serratosa J.M., Rosenow F., Feucht M., Unterberger I., Covanis A., Suls A., Weckhuysen S., Kaneva R., Caglayan H., Turkdogan D., Baykan B., Bebek N., Ozbek U., Hempelmann A., Schulz H., Rüschendorf F., Trucks H., Nürnberg P., Avanzini G., Koeleman B.P., Sander T., and Tinuper P.

Subjects
Male, Chromosomes, Human, Pair 13, Genotype, Genetic Linkage, Chromosome Mapping, complex inheritance, Pedigree, genetic generalized epilepsy, myoclonic seizure, Phenotype, Genetic Loci, Chromosomes, Human, Pair 2, Humans, Epilepsy, Generalized, Family, Female, Genetic Predisposition to Disease, linkage analysis, absence seizure, Genome-Wide Association Study
Abstract

PURPOSE: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. METHODS: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. KEY FINDINGS: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). SIGNIFICANCE: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.

Published
2012

27. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Author

Leu C, de Kovel CG, Zara F, Striano P, Pezzella M, Robbiano A, Bianchi A, Bisulli F, Coppola A, Giallonardo AT, Beccaria F, Trenité DK, Lindhout D, Gaus V, Schmitz B, Janz D, Weber YG, Becker F, Lerche H, Kleefuss Lie AA, Hallman K, Kunz WS, Elger CE, Muhle H, Stephani U, Møller RS, Hjalgrim H, Mullen S, Scheffer IE, Berkovic SF, Everett KV, Gardiner MR, Marini C, Guerrini R, Lehesjoki AE, Siren A, Nabbout R, Baulac S, Leguern E, Serratosa JM, Rosenow F, Feucht M, Unterberger I, Covanis A, Suls A, Weckhuysen S, Kaneva R, Caglayan H, Turkdogan D, Baykan B, Bebek N, Ozbek U, Hempelmann A, Schulz H, Rüschendorf F, Trucks H, Nürnberg P, Avanzini G, Koeleman BP, Sander T, EPICURE Consortium, COPPOLA, ANTONIETTA, DEL GIUDICE, ENNIO, Leu, C, de Kovel, Cg, Zara, F, Striano, P, Pezzella, M, Robbiano, A, Bianchi, A, Bisulli, F, Coppola, A, Giallonardo, At, Beccaria, F, Trenité, Dk, Lindhout, D, Gaus, V, Schmitz, B, Janz, D, Weber, Yg, Becker, F, Lerche, H, Kleefuss Lie, Aa, Hallman, K, Kunz, W, Elger, Ce, Muhle, H, Stephani, U, Møller, R, Hjalgrim, H, Mullen, S, Scheffer, Ie, Berkovic, Sf, Everett, Kv, Gardiner, Mr, Marini, C, Guerrini, R, Lehesjoki, Ae, Siren, A, Nabbout, R, Baulac, S, Leguern, E, Serratosa, Jm, Rosenow, F, Feucht, M, Unterberger, I, Covanis, A, Suls, A, Weckhuysen, S, Kaneva, R, Caglayan, H, Turkdogan, D, Baykan, B, Bebek, N, Ozbek, U, Hempelmann, A, Schulz, H, Rüschendorf, F, Trucks, H, Nürnberg, P, Avanzini, G, Koeleman, Bp, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, and Coppola, Antonietta

Published
2012

32. A certified plasmid reference material for the standardisation of BCR-ABL1 mRNA quantification by real-time quantitative PCR

Author

White, H., Deprez, L., Corbisier, P., Hall, V., Lin, F., Mazoua, S., Trapmann, S., Aggerholm, A., Andrikovics, H., Akiki, S., Barbany, G., Boeckx, N., Bench, A., Catherwood, M., Cayuela, J-M, Chudleigh, S., Clench, T., Colomer, D., Daraio, F., Dulucq, S., Farrugia, J., Fletcher, L., Foroni, L., Ganderton, R., Gerrard, G., Gineikiene, E., Hayette, S., El Housni, H., Izzo, B., Jansson, Mattias, Johnels, P., Jurcek, T., Kairisto, V., Kizilors, A., Kim, D-W, Lange, T., Lion, T., Polakova, K. M., Martinelli, G., McCarron, S., Merle, P. A., Milner, B., Mitterbauer-Hohendanner, G., Nagar, M., Nickless, G., Nomdedeu, J., Nymoen, D. A., Leibundgut, E. O., Ozbek, U., Pajic, T., Pfeifer, H., Preudhomme, C., Raudsepp, K., Romeo, G., Sacha, T., Talmaci, R., Touloumenidou, T., Van der Velden, V. H. J., Waits, P., Wang, L., Wilkinson, E., Wilson, G., Wren, D., Zadro, R., Ziermann, J., Zoi, K., Mueller, M. C., Hochhaus, A., Schimmel, H., Cross, N. C. P., Emons, H., White, H., Deprez, L., Corbisier, P., Hall, V., Lin, F., Mazoua, S., Trapmann, S., Aggerholm, A., Andrikovics, H., Akiki, S., Barbany, G., Boeckx, N., Bench, A., Catherwood, M., Cayuela, J-M, Chudleigh, S., Clench, T., Colomer, D., Daraio, F., Dulucq, S., Farrugia, J., Fletcher, L., Foroni, L., Ganderton, R., Gerrard, G., Gineikiene, E., Hayette, S., El Housni, H., Izzo, B., Jansson, Mattias, Johnels, P., Jurcek, T., Kairisto, V., Kizilors, A., Kim, D-W, Lange, T., Lion, T., Polakova, K. M., Martinelli, G., McCarron, S., Merle, P. A., Milner, B., Mitterbauer-Hohendanner, G., Nagar, M., Nickless, G., Nomdedeu, J., Nymoen, D. A., Leibundgut, E. O., Ozbek, U., Pajic, T., Pfeifer, H., Preudhomme, C., Raudsepp, K., Romeo, G., Sacha, T., Talmaci, R., Touloumenidou, T., Van der Velden, V. H. J., Waits, P., Wang, L., Wilkinson, E., Wilson, G., Wren, D., Zadro, R., Ziermann, J., Zoi, K., Mueller, M. C., Hochhaus, A., Schimmel, H., Cross, N. C. P., and Emons, H.

Abstract

Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukaemia, but there is a substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08 +/- 0.13 x 10(6), 1.08 +/- 0.11 x 10(5), 1.03 +/- 0.10 x 10(4), 1.02 +/- 0.09 x 10(3), 1.04 +/- 0.10 x 10(2) and 10.0 +/- 1.5 copies/mu l. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise a number of measured transcripts of e14a2 BCR-ABL1 and three control genes (ABL1, BCR and GUSB). The set of six plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (https://ec.europa.eu/jrc/en/reference-materials/catalogue/;CRM code ERM-AD623a-f).

Published
2015
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35. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1,2q22.3 and 17q21.32

Author

Steffens, M., Leu, C., Ruppert, A., Zara, F., Striano, P., Robbiano, A., Capovilla, G., Tinuper, P., Gambardella, A., Bianchi, A., La neve, A., Crichiutti, G., de kovel, C. G., Trenité, D. K. -N., de haan, G., Lindhout, D., Gaus, V., Schmitz, B., Janz, D., Weber, Y. G., Becker, F., Lerche, H., Steinhoff, B. J., Kleefuß-Lie, A. A., Kunz, W. S., Surges, R., Elger, C. E., Muhle, H., Von spiczak, S., Ostertag, P., Helbig, I., Stephani, U., Møller, R. S., Hjalgrim, H., Dibbens, L. M., Bellows, S., Oliver, K., Mullen, S., Scheffer, I. E., Berkovic, S. F., Everett, K. V., Gardiner, M. R., Marini, Chiara, Guerrini, R., Lehesjoki, A., Siren, A., Guipponi, M., Malafosse, A., Thomas, P., Nabbout, R., Baulac, S., Leguern, E., Guerrero, R., Serratosa, J. M., Reif, P. S., Rosenow, F., Mörzinger, M., Feucht, M., Zimprich, F., Kapser, C., Schankin, C. J., Suls, A., Smets, K., De jonghe, P., Jordanova, A., Caglayan, H., Yapici, Z., Yalcin, D. A., Baykan, B., Bebek, N., Ozbek, U., Gieger, C., Wichmann, H., Balschun, T., Ellinghaus, D., Franke, A., Meesters, C., Becker, T., Wienker, T. F., Hempelmann, A., Schulz, H., Rüschendorf, F., Leber, M., Pauck, S. M., Trucks, H., Toliat, M. R., Nürnberg, P., Avanzini, G., Koeleman, B. P., Sander, T., Weckhuysen, S., Claes, L., Deprez, L., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Lehesjoki, A. -E., von Spiczak, S., Martin Klein, K., Oertel, W. H., Hamer, H. M., Marini, C., Mei, D., Norci, V., Pezzella, M., La Neve, A., Vigliano, P., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Egeo, G., Teresa Giallonardo, M., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., de Haan, G. -J., Giraldez, B. G., Ozbeck, U., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Ozkara, C., Yalcin, O., Turkdogan, D., Dizdarer, G., Agan, K., Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Frederico, Dibbens, Leanne Michelle, Sander, Thomas, EPICURE Consortium, Epicure, Consortium, DEL GIUDICE, Ennio, Steffens, M, Leu, C, Ruppert, Ak, Zara, F, Striano, P, Robbiano, A., Coppola, Antonietta, E. P. I. C. U. R. E. Consortium, E. M. I.Net Consortium, M. Steffen, C. Leu, A. Ruppert, F. Zara, P. Striano, A. Robbiano, G. Capovilla, P. Tinuper, A. Gambardella, A. Bianchi, A. L. Neve, G. Crichiutti, C. G. F, D. K. Trenité, G. d. Haan, D. Lindhout, V. Gau, B. Schmitz, D. Janz, Y. G. Weber, F. Becker, H. Lerche, B. J. Steinhoff, A. A. Kleefuß-Lie, W. S. Kunz, R. Surge, C. E. Elger, H. Muhle, S. v. Spiczak, P. Ostertag, I. Helbig, U. Stephani, R. S. Møller, H. Hjalgrim, L. M. Dibben, S. Bellow, K. Oliver, S. Mullen, I. E. Scheffer, S. F. Berkovic, K. V. Everett, M. R. Gardiner, C. Marini, R. Guerrini, A. Lehesjoki, A. Siren, M. Guipponi, A. Malafosse, P. Thoma, R. Nabbout, S. Baulac, E. Leguern, R. Guerrero, J. M. Serratosa, P. S. Reif, F. Rosenow, M. Mörzinger, M. Feucht, F. Zimprich, C. Kapser, C. J. Schankin, A. Sul, K. Smet, P. D. Jonghe, A. Jordanova, H. Caglayan, Z. Yapici, D. A. Yalcin, B. Baykan, N. Bebek, U. Ozbek, C. Gieger, H. Wichmann, T. Balschun, D. Ellinghau, A. Franke, C. Meester, T. Becker, T. F. Wienker, A. Hempelmann, H. Schulz, F. Rüschendorf, M. Leber, S. M. Pauck, H. Truck, M. R. Toliat, P. Nürnberg, G. Avanzini, B. P. C, and T. Sander

Subjects
Candidate gene, Juvenile, Genome-wide association study, Alleles, Epilepsy, ZEB2 protein, human, VRK2 protein, human, 0302 clinical medicine, genetics [Genetic Predisposition to Disease], genetics, Humans, Myoclonic Epilepsy, genetics [Epilepsy, Generalized], SCN1A protein, human, Genetics (clinical), Genetics, 0303 health sciences, genetics [Epilepsy, Absence], Myoclonic Epilepsy, Juvenile, genetics, Genetic Predisposition to Disease, General Medicine, Protein-Serine-Threonine Kinases, 3. Good health, Chemistry, Absence, genetics, Epilepsy, genetics [Myoclonic Epilepsy, Juvenile], Epilepsy, Generalized, genetics [Receptor, Muscarinic M3], genetics, NAV1.1 Voltage-Gated Sodium Channel, genetics [Homeodomain Proteins], Single-nucleotide polymorphism, genetics [NAV1.1 Voltage-Gated Sodium Channel], Protein Serine-Threonine Kinases, Biology, genetics [Protein-Serine-Threonine Kinases], 03 medical and health sciences, ddc:570, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, genetics, Repressor Protein, Allele, Molecular Biology, Alleles, Zinc Finger E-box Binding Homeobox 2, 030304 developmental biology, Homeodomain Proteins, Receptor, Muscarinic M3, genetics, Protein-Serine-Threonine Kinase, genetics, Receptor, Generalized, genetics, Genome-Wide Association Study, Homeodomain Protein, Heritability, medicine.disease, NAV1.1 Voltage-Gated Sodium Channel, Repressor Proteins, genetics [Repressor Proteins], Muscarinic M3, Epilepsy, Absence, Myoclonic epilepsy, Human medicine, Juvenile myoclonic epilepsy, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3\% and account for 20-30\% of all epilepsies. Despite their high heritability of 80\%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Published
2012

36. Investigation of the Relationship Between Clinical and EEG Findings of Photosensitive Epilepsy and GABA Receptor Alpha 1 Subunit (GABRA1) Gene Mutations

Author

Yavuz, E.N., Demirkan, A., Moen, S., Ozdemir, O., Catal, S., Bebek, N., Ozbek, U., Baykan, B., and Faculteit der Geneeskunde

Abstract

Objective: Although photosensitive epilepsy (PE) is commonly observed, its pathophysiology has not been clarified yet. However, relevant literature indicates that genetic factors play an important role. Our aim was to investigate whether there is a relationship between the clinical and electroencephalographic (EEG) features and the possible mutations/polymorphisms in the GABA receptor alpha 1 subunit (GABRA1) gene in patients with PE by scanning this gene. Methods: 54 patients diagnosed as having PE according to International League Against Epilepsy (ILAE) criteria were included in the study. The patients were analyzed in terms of gender, clinical and syndromic features, response to treatment, EEG features, and photoparoxysmal response (PPR) types. Mutation screening was done by denaturing high-performance liquid chromatography (DHPLC) on all exons belonging to GABRA1 gene. Results: We could not detect any mutation in GABRA1 gene in patients with PE. Four single-nucleotide polymorphisms (SNPs) in GABRA1 gene were observed, but none of them were associated with amino acid changes. Besides, when comparing the patients having these SNPs with the remaining patients without any SNPs in regard to clinical and EEG features, we were not able to find a statistically significant difference for GABRA1 gene. Conclusion: The lack of mutations in the GABRA1 gene indicates that this gene is not predominantly involved in the etiopathogenesis of PE in the Turkish population. In order to get more precise evidence, the research should be extended by increasing the number of patients and by investigating other genes related to GABA. (Archives of Neuropsychiatry 2011; 48: 39-43)

Published
2011

40. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment ofhigh-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNetStudy

Author

Baccarani, M, Rosti, G, Castagnetti, F, Haznedaroglu, I, Porkka, K, Abruzzese, E, Alimena, G, Ehrencrona, H, Hjorth Hansen, H, Kairisto, V, Levato, L, Martinelli, G, Nagler, A, Lanng Nielsen, J, Ozbek, U, Palandri, F, Palmieri, F, Pane, F, Rege Cambrin, G, Russo, D, Specchia, G, Testoni, N, Weiss Bjerrum, O, Saglio, Giuseppe, and Simonsson, B.

Published
2009

41. Seroreactivity against PTEN-induced putative kinase 1 (PINK1) in Turkish patients with Behçet's disease

Author

Vural B, Ayse Demirkan, Ugurel E, Kalaylioglu-Wheeler Z, Ba, Esen, Ao, Gure, Gül A, and Ozbek U

Subjects
Adult, Male, Turkey, Behcet Syndrome, PINK1, Vesicular Transport Proteins, Nuclear Proteins, Proteins, RNA-Binding Proteins, Medical sciences, DNA-Binding Proteins, Minor Histocompatibility Antigens, Behçet’s disease, Rheumatology, Autoantigen, SWAP70, Guanine Nucleotide Exchange Factors, Humans, Female, Apoptosis Regulatory Proteins, Protein Kinases, Autoantibodies, Gene Library, ANKRDA1
Abstract

Behçet's disease (BD) is a multisystem inflammatory disorder characterized by recurrent oral ulcers, genital ulcers and ocular inflammation, as well as skin, joint, vascular, pulmonary, central nervous system (CNS) and gastrointestinal tract manifestations. The etiopathogenesis of BD has not yet been identified; but it has generally been accepted that several environmental factors may induce an inflammatory attack in genetically susceptible individuals. In this study, we aimed to identify antigens that could elicit high-titer IgG responses by the serological analysis of recombinant expression of cDNA libraries method (SEREX).We screened a human testis cDNA library with pooled sera obtained from 4 BD patients by SEREX. Antigens that were identified with the initial analysis were selected for seroreactivity analysis of a larger group of BD patients (n=78) and controls (n=66) by serological immunoscreening.We observed seroreactivity against 6 antigens using the pooled sera. These included rabaptin 5 (RABPT5), PTEN-induced putative kinase 1 (PINK1), switch associated protein 70 (SWAP70), interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), ankyrin repeat domain 20 family, member A1 (ANKRD20A1), and an unknown antigen. Eleven out of 82 (13.4%) BD patients were found to have antibodies elicited against PINK1 antigen, when none of the control sera showed reactivity (p=0.001). There was no significant difference in the frequency of other defined antigens between the patient and control groups. However, among BD clinical sub-groups, anti-SWAP70 antibodies were found to associate with vascular involvement.In this study, antibodies against PINK1 were found to specifically associate with BD while SWAP70 antibody was associated with clinical sub-groups of BD. Although variations in both genetic background and environmental factors may affect the outcome of serological responses, our results suggest that serological screening can be used to identify antigens that elicit antibody responses associated with BD.

Published
2009

42. A comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of patients with high risk, Ph-pos, chronic myeloid leukemia. An ELN Study

Author

Baccarani, M., Rosti, G., Castagnetti, F., Haznedaroglu, I., Porkka, K., Abruzzese, E., Alimena, G., Amabile, M., Boström, H., Hjorth Hansen, H., Kairisto, V., Levato, L., Martinelli, G., Nagler, A., Lanng Nielsen, J., Ozbek, U., Palandri, F., Palmieri, F., Pane, F., Rege Cambrin, G., Russo, Domenico, Specchia, G., Testoni, N., Weiss Bjerrum, O., Saglio, G., and Simonsson, B.

Published
2009

44. A certified plasmid reference material for the standardisation of BCR–ABL1 mRNA quantification by real-time quantitative PCR

Author

White, H, primary, Deprez, L, additional, Corbisier, P, additional, Hall, V, additional, Lin, F, additional, Mazoua, S, additional, Trapmann, S, additional, Aggerholm, A, additional, Andrikovics, H, additional, Akiki, S, additional, Barbany, G, additional, Boeckx, N, additional, Bench, A, additional, Catherwood, M, additional, Cayuela, J-M, additional, Chudleigh, S, additional, Clench, T, additional, Colomer, D, additional, Daraio, F, additional, Dulucq, S, additional, Farrugia, J, additional, Fletcher, L, additional, Foroni, L, additional, Ganderton, R, additional, Gerrard, G, additional, Gineikienė, E, additional, Hayette, S, additional, El Housni, H, additional, Izzo, B, additional, Jansson, M, additional, Johnels, P, additional, Jurcek, T, additional, Kairisto, V, additional, Kizilors, A, additional, Kim, D-W, additional, Lange, T, additional, Lion, T, additional, Polakova, K M, additional, Martinelli, G, additional, McCarron, S, additional, Merle, P A, additional, Milner, B, additional, Mitterbauer-Hohendanner, G, additional, Nagar, M, additional, Nickless, G, additional, Nomdedéu, J, additional, Nymoen, D A, additional, Leibundgut, E O, additional, Ozbek, U, additional, Pajič, T, additional, Pfeifer, H, additional, Preudhomme, C, additional, Raudsepp, K, additional, Romeo, G, additional, Sacha, T, additional, Talmaci, R, additional, Touloumenidou, T, additional, Van der Velden, V H J, additional, Waits, P, additional, Wang, L, additional, Wilkinson, E, additional, Wilson, G, additional, Wren, D, additional, Zadro, R, additional, Ziermann, J, additional, Zoi, K, additional, Müller, M C, additional, Hochhaus, A, additional, Schimmel, H, additional, Cross, N C P, additional, and Emons, H, additional

Published
2014
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45. Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia

Author

Ng, O H, primary, Erbilgin, Y, additional, Firtina, S, additional, Celkan, T, additional, Karakas, Z, additional, Aydogan, G, additional, Turkkan, E, additional, Yildirmak, Y, additional, Timur, C, additional, Zengin, E, additional, van Dongen, J J M, additional, Staal, F J T, additional, Ozbek, U, additional, and Sayitoglu, M, additional

Published
2014
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46. Expression analysis and clinical correlation of aquaporin 1 and 4 genes in human hippocampal sclerosis

Author

Bebek, N., primary, Özdemir, Ö., additional, Sayitoglu, M., additional, Hatırnaz, Ö., additional, Baykan, B., additional, Gürses, C., additional, Sencer, A., additional, Karasu, A., additional, Tüzün, E., additional, Üzün, I., additional, Akat, S., additional, Cine, N., additional, Sargin Kurt, G., additional, Imer, M., additional, Ozbek, U., additional, Canbolat, A., additional, and Gökyigit, A., additional

Published
2013
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47. The nuclear effector of wnt-signaling, tcf1, functions as a T-cell-specific tumor suppressor for development of lymphomas

Author

Tiemessen, M.M., Baert, M.R., Schonewille, T., Brugman, M.H., Famili, F., Salvatori, D.C., Meijerink, J.P., Ozbek, U., Clevers, H., van Dongen, J.J., Staal, F.J., Tiemessen, M.M., Baert, M.R., Schonewille, T., Brugman, M.H., Famili, F., Salvatori, D.C., Meijerink, J.P., Ozbek, U., Clevers, H., van Dongen, J.J., and Staal, F.J.

Abstract

The HMG-box factor Tcf1 is required during T-cell development in the thymus and mediates the nuclear response to Wnt signals. Tcf1(-/-) mice have previously been characterized and show developmental blocks at the CD4-CD8- double negative (DN) to CD4+CD8+ double positive transition. Due to the blocks in T-cell development, Tcf1(-/-) mice normally have a very small thymus. Unexpectedly, a large proportion of Tcf1(-/-) mice spontaneously develop thymic lymphomas with 50% of mice developing a thymic lymphoma/leukemia at the age of 16 wk. These lymphomas are clonal, highly metastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and have high expression of Wnt target genes Lef1 and Axin2. In wild-type thymocytes, Tcf1 is higher expressed than Lef1, with a predominance of Wnt inhibitory isoforms. Loss of Tcf1 as repressor of Lef1 leads to high Wnt activity and is the initiating event in lymphoma development, which is exacerbated by activating Notch1 mutations. Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events. Tcf1 deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due to lack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1. Tcf1 therefore functions as a T-cell-specific tumor suppressor gene, besides its established role as a Wnt responsive transcription factor. Thus, Tcf1 acts as a molecular switch between proliferative and repressive signals during T-lymphocyte development in the thymus., The HMG-box factor Tcf1 is required during T-cell development in the thymus and mediates the nuclear response to Wnt signals. Tcf1(-/-) mice have previously been characterized and show developmental blocks at the CD4-CD8- double negative (DN) to CD4+CD8+ double positive transition. Due to the blocks in T-cell development, Tcf1(-/-) mice normally have a very small thymus. Unexpectedly, a large proportion of Tcf1(-/-) mice spontaneously develop thymic lymphomas with 50% of mice developing a thymic lymphoma/leukemia at the age of 16 wk. These lymphomas are clonal, highly metastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and have high expression of Wnt target genes Lef1 and Axin2. In wild-type thymocytes, Tcf1 is higher expressed than Lef1, with a predominance of Wnt inhibitory isoforms. Loss of Tcf1 as repressor of Lef1 leads to high Wnt activity and is the initiating event in lymphoma development, which is exacerbated by activating Notch1 mutations. Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events. Tcf1 deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due to lack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1. Tcf1 therefore functions as a T-cell-specific tumor suppressor gene, besides its established role as a Wnt responsive transcription factor. Thus, Tcf1 acts as a molecular switch between proliferative and repressive signals during T-lymphocyte development in the thymus.

Published
2012

48. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Author

Steffens, M, Leu, C, Ruppert, A-K, Zara, F, Striano, P, Robbiano, A, Capovilla, G, Tinuper, P, Gambardella, A, Bianchi, A, La Neve, A, Crichiutti, G, de Kovel, CGF, Trenite, DK-N, de Haan, G-J, Lindhout, D, Gaus, V, Schmitz, B, Janz, D, Weber, YG, Becker, F, Lerche, H, Steinhoff, BJ, Kleefuss-Lie, AA, Kunz, WS, Surges, R, Elger, CE, Muhle, H, von Spiczak, S, Ostertag, P, Helbig, I, Stephani, U, Moller, RS, Hjalgrim, H, Dibbens, LM, Bellows, S, Oliver, K, Mullen, S, Scheffer, IE, Berkovic, SF, Everett, KV, Gardiner, MR, Marini, C, Guerrini, R, Lehesjoki, A-E, Siren, A, Guipponi, M, Malafosse, A, Thomas, P, Nabbout, R, Baulac, S, Leguern, E, Guerrero, R, Serratosa, JM, Reif, PS, Rosenow, F, Moerzinger, M, Feucht, M, Zimprich, F, Kapser, C, Schankin, CJ, Suls, A, Smets, K, De Jonghe, P, Jordanova, A, Caglayan, H, Yapici, Z, Yalcin, DA, Baykan, B, Bebek, N, Ozbek, U, Gieger, C, Wichmann, H-E, Balschun, T, Ellinghaus, D, Franke, A, Meesters, C, Becker, T, Wienker, TF, Hempelmann, A, Schulz, H, Rueschendorf, F, Leber, M, Pauck, SM, Trucks, H, Toliat, MR, Nuernberg, P, Avanzini, G, Koeleman, BPC, Sander, T, Steffens, M, Leu, C, Ruppert, A-K, Zara, F, Striano, P, Robbiano, A, Capovilla, G, Tinuper, P, Gambardella, A, Bianchi, A, La Neve, A, Crichiutti, G, de Kovel, CGF, Trenite, DK-N, de Haan, G-J, Lindhout, D, Gaus, V, Schmitz, B, Janz, D, Weber, YG, Becker, F, Lerche, H, Steinhoff, BJ, Kleefuss-Lie, AA, Kunz, WS, Surges, R, Elger, CE, Muhle, H, von Spiczak, S, Ostertag, P, Helbig, I, Stephani, U, Moller, RS, Hjalgrim, H, Dibbens, LM, Bellows, S, Oliver, K, Mullen, S, Scheffer, IE, Berkovic, SF, Everett, KV, Gardiner, MR, Marini, C, Guerrini, R, Lehesjoki, A-E, Siren, A, Guipponi, M, Malafosse, A, Thomas, P, Nabbout, R, Baulac, S, Leguern, E, Guerrero, R, Serratosa, JM, Reif, PS, Rosenow, F, Moerzinger, M, Feucht, M, Zimprich, F, Kapser, C, Schankin, CJ, Suls, A, Smets, K, De Jonghe, P, Jordanova, A, Caglayan, H, Yapici, Z, Yalcin, DA, Baykan, B, Bebek, N, Ozbek, U, Gieger, C, Wichmann, H-E, Balschun, T, Ellinghaus, D, Franke, A, Meesters, C, Becker, T, Wienker, TF, Hempelmann, A, Schulz, H, Rueschendorf, F, Leber, M, Pauck, SM, Trucks, H, Toliat, MR, Nuernberg, P, Avanzini, G, Koeleman, BPC, and Sander, T

Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Published
2012

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