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201. AUNA2: A Novel Type of Non-Syndromic Slowly Progressive Auditory Synaptopathy/Auditory Neuropathy with Autosomal-Dominant Inheritance

Author

Lang-Roth, Ruth, Fischer-Krall, Eva, Kornblum, Cornelia, Nuernberg, Gudrun, Meschede, Dieter, Goebel, Ingrid, Nuernberg, Peter, Beutner, Dirk, Kubisch, Christian, Walger, Martin, Volk, Alexander E., Lang-Roth, Ruth, Fischer-Krall, Eva, Kornblum, Cornelia, Nuernberg, Gudrun, Meschede, Dieter, Goebel, Ingrid, Nuernberg, Peter, Beutner, Dirk, Kubisch, Christian, Walger, Martin, and Volk, Alexander E.

Abstract

Background: Auditory synaptopathy/neuropathy (AS/AN) is a heterogeneous disorder, which may be caused by environmental factors like postnatal hyperbilirubinemia or by genetic factors. The genetic forms are subdivided into syndromic and non-syndromic types, and show different inheritance patterns with a strong preponderance of autosomal-recessive forms. To date, only a single locus for non-syndromic autosomal-dominant AS/AN (AUNA1) has been reported in a single family, in which a non-coding DIAPH3 mutation was subsequently described as causative. Materials and Methods: Here, we report detailed clinical data on a large German AS/AN family with slowly progressive postlingual hearing loss. Affected family members developed their first symptoms in their second decade. Mod erate hearing loss in the fourth decade then progressed to profound hearing impairment in older family members. Comprehensive audiological and neurological tests were performed in the affected family members. Genetic testing comprised linkage analyses with polymorphic markers and a genome-wide linkage analysis using the Affymetrix GeneChip (R) Human Mapping 250K. Results and Conclusion: We identified a large family with autosomal-dominant AS/AN. By means of linkage analyses, the AUNA1 locus was excluded, and putatively linked regions on chromosomal bands 12q24 and 13q34 were identified as likely carrying the second locus for autosomal-dominant AS/AN (AUNA2). AUNA2 is associated with a slowly progressive postlingual hearing loss without any evidence for additional symptoms in other organ systems. (C) 2017 S. Karger AG, Basel

Published
2017

202. WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects

Author

Yokote, Koutaro, Chanprasert, Sirisak, Lee, Lin, Eirich, Katharina, Takemoto, Minoru, Watanabe, Aki, Koizumi, Naoko, Lessel, Davor, Mori, Takayasu, Hisama, Fuki M., Ladd, Paula D., Angle, Brad, Baris, Hagit, Cefle, Kivanc, Palanduz, Sukru, Ozturk, Sukru, Chateau, Antoinette, Deguchi, Kentaro, Easwar, T.K.M, Federico, Antonio, Fox, Amy, Grebe, Theresa A., Hay, Beverly, Nampoothiri, Sheela, Seiter, Karen, Streeten, Elizabeth, Piña-Aguilar, Raul E., Poke, Gemma, Poot, Martin, Posmyk, Renata, Martin, George M., Kubisch, Christian, Schindler, Detlev, and Oshima, Junko

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Polymorphism, Genetic, Werner Syndrome Helicase, Geography, Age Factors, nutritional and metabolic diseases, Exons, Web Browser, Polymorphism, Single Nucleotide, Article, Translational Research, Biomedical, Disease Models, Animal, Mice, Phenotype, Gene Frequency, Japan, Databases, Genetic, Mutation, Animals, Humans, Genetic Predisposition to Disease, Registries, Werner Syndrome, Genetic Association Studies
Abstract

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

Published
2016

203. The analysis of heterotaxy patients reveals new loss-of-function variants of GRK5

Author

Lessel, Davor, Muhammad, Tariq, Casar Tena, Teresa, Moepps, Barbara, Burkhalter, Martin D., Hitz, Marc-Phillip, Toka, Okan, Rentzsch, Axel, Schubert, Stephan, Schalinski, Adelheid, Bauer, Ulrike M. M., Kubisch, Christian, Ware, Stephanie M., and Philipp, Melanie

Subjects
G-Protein-Coupled Receptor Kinase 5, Male, Embryo, Nonmammalian, Sequence Homology, Amino Acid, Heterotaxy Syndrome, Zebrafish Proteins, Polymorphism, Single Nucleotide, Article, HEK293 Cells, Gene Frequency, Loss of Function Mutation, Animals, Humans, Female, Genetic Predisposition to Disease, Amino Acid Sequence, In Situ Hybridization, Zebrafish
Abstract

G protein-coupled receptor kinase 5 (GRK5) is a regulator of cardiac performance and a potential therapeutic target in heart failure in the adult. Additionally, we have previously classified GRK5 as a determinant of left-right asymmetry and proper heart development using zebrafish. We thus aimed to identify GRK5 variants of functional significance by analysing 187 individuals with laterality defects (heterotaxy) that were associated with a congenital heart defect (CHD). Using Sanger sequencing we identified two moderately frequent variants in GRK5 with minor allele frequencies

Published
2016
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204. Familiäre progrediente Ertaubung durch neue Mutation im ACTG1-Gen

Author

Fischer-Krall, Eva, Beutner, Dirk, Lang-Roth, Ruth, Setz, Cristian, Goebel, Ingrid, Thiele, Holger, Nuernberg, Peter, Kubisch, Christian, and Volk, Alexander Erich

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Hintergrund Familiäre progrediente Schwerhörigkeiten sind eine heterogene Gruppe von Hörstörungen hinsichtlich der klinischen Charakteristika und der zu Grunde liegenden Genetik. Sie unterscheiden sich bezüglich der primär betroffenen Frequenzbereiche, des zeitlichen[zum vollständigen Text gelangen Sie über die oben angegebene URL], 33. Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Phoniatrie und Pädaudiologie (DGPP)

Published
2016

205. Horizontal gaze palsy with progressive scoliosis: Three novel ROBO3 mutations and descriptions of the phenotypes of four patients

Author

Volk, Alexander E., Carter, Oliver, Fricke, Julia, Herkenrath, Peter, Poggenborg, Jörg, Borck, Guntram, Demant, Andre W., Ivo, Roland, Eysel, Peer, Kubisch, Christian, and Neugebauer, Antje

Subjects
Male, Adolescent, Base Sequence, Turkey, Siblings, Vision Tests, DNA Mutational Analysis, Molecular Sequence Data, Saudi Arabia, Receptors, Cell Surface, Magnetic Resonance Imaging, Pedigree, Consanguinity, Early Diagnosis, Ocular Motility Disorders, Phenotype, Scoliosis, Mutation, Humans, Female, Receptors, Immunologic, Child, Research Article
Abstract

Purpose Clinical and molecular characterization of patients with horizontal gaze palsy with progressive scoliosis (HGPPS) to extend existing knowledge of the phenotype caused by mutations in the Roundabout homolog of Drosophila 3 (ROBO3) gene. Methods Four patients (aged 6 months to 13 years), two of them siblings, with features of horizontal gaze palsy and their parents were examined clinically and by molecular testing of the ROBO3 gene. The three families were unrelated, but parents in each family were consanguineous. Results We identified three novel homozygous ROBO3 mutations in four patients with typical ophthalmologic signs of HGPPS. We found an exonic insertion/deletion mutation (c.913delAinsTGC; p.Ile305CysfsX13), a 31 bp deletion including the donor splice site of exon 17 and adjacent exonic and intronic sequences (c.2769_2779del11, 2779+1_+20del20), and a missense mutation located next to a splice donor site (c.3319A>C) resulting in skipping of exon 22, as shown by cDNA analysis. Conclusions We describe three novel mutations in the ROBO3 gene and the detailed clinical phenotype of HGPPS. One patient displayed marked convergence upon attempting smooth pursuits to both sides. In one patient, the typical ophthalmologic phenotype, the neuroradiologic findings, and molecular testing led to the diagnosis even before scoliosis developed. In addition to the typical magnetic resonance imaging brain signs of HGPPS, this patient had marked hypoplasia of the frontal lobes and corpus callosum. In summary, diagnosis of HGPPS may be established by ophthalmologic and molecular investigation early in life, allowing ongoing orthopedic surveillance from an early stage.

Published
2011

206. De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Author

Lessel, Davor, primary, Schob, Claudia, additional, Küry, Sébastien, additional, Reijnders, Margot R.F., additional, Harel, Tamar, additional, Eldomery, Mohammad K., additional, Coban-Akdemir, Zeynep, additional, Denecke, Jonas, additional, Edvardson, Shimon, additional, Colin, Estelle, additional, Stegmann, Alexander P.A., additional, Gerkes, Erica H., additional, Tessarech, Marine, additional, Bonneau, Dominique, additional, Barth, Magalie, additional, Besnard, Thomas, additional, Cogné, Benjamin, additional, Revah-Politi, Anya, additional, Strom, Tim M., additional, Rosenfeld, Jill A., additional, Yang, Yaping, additional, Posey, Jennifer E., additional, Immken, LaDonna, additional, Oundjian, Nelly, additional, Helbig, Katherine L., additional, Meeks, Naomi, additional, Zegar, Kelsey, additional, Morton, Jenny, additional, Schieving, Jolanda H., additional, Claasen, Ana, additional, Huentelman, Matthew, additional, Narayanan, Vinodh, additional, Ramsey, Keri, additional, Brunner, Han G., additional, Elpeleg, Orly, additional, Mercier, Sandra, additional, Bézieau, Stéphane, additional, Kubisch, Christian, additional, Kleefstra, Tjitske, additional, Kindler, Stefan, additional, Lupski, James R., additional, and Kreienkamp, Hans-Jürgen, additional

Published
2017
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207. The role of de novo mutations in the development of amyotrophic lateral sclerosis

Author

Doormaal, Perry T.C., primary, Ticozzi, Nicola, additional, Weishaupt, Jochen H., additional, Kenna, Kevin, additional, Diekstra, Frank P., additional, Verde, Federico, additional, Andersen, Peter M., additional, Dekker, Annelot M., additional, Tiloca, Cinzia, additional, Marroquin, Nicolai, additional, Overste, Daniel J., additional, Pensato, Viviana, additional, Nürnberg, Peter, additional, Pulit, Sara L., additional, Schellevis, Raymond D., additional, Calini, Daniela, additional, Altmüller, Janine, additional, Francioli, Laurent C., additional, Muller, Bernard, additional, Castellotti, Barbara, additional, Motameny, Susanne, additional, Ratti, Antonia, additional, Wolf, Joachim, additional, Gellera, Cinzia, additional, Ludolph, Albert C., additional, den Berg, Leonard H., additional, Kubisch, Christian, additional, Landers, John E., additional, Veldink, Jan H., additional, Silani, Vincenzo, additional, and Volk, Alexander E., additional

Published
2017
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208. AUNA2: A Novel Type of Non-Syndromic Slowly Progressive Auditory Synaptopathy/Auditory Neuropathy with Autosomal-Dominant Inheritance

Author

Lang-Roth, Ruth, primary, Fischer-Krall, Eva, additional, Kornblum, Cornelia, additional, Nürnberg, Gudrun, additional, Meschede, Dieter, additional, Goebel, Ingrid, additional, Nürnberg, Peter, additional, Beutner, Dirk, additional, Kubisch, Christian, additional, Walger, Martin, additional, and Volk, Alexander E., additional

Published
2017
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209. Effects of Pharmacological Blockade and Genotype of Serotonin Transporters on Response Inhibition and Post Error Slowing

Author

Ullsperger Markus, Fischer Adrian, Kubisch Christian, and Reuter Martin

Subjects
medicine.medical_specialty, business.industry, Transporter, Pharmacology, Blockade, Behavioral Neuroscience, Psychiatry and Mental health, Endocrinology, Neuropsychology and Physiological Psychology, Neurology, Internal medicine, Genotype, medicine, Serotonin, business, Response inhibition, Biological Psychiatry
Published
2015
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211. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients

Author

Medicina, Neurociencias, Medikuntza, Neurozientziak, Sadovnick, A. Dessa, Traboulsee, Anthony L., Bernales, Cecily Q., Ross, Jay P., Forwell, Amanda L., Yee, Irene M., Guillot-Noel, Lena, Fontaine, Bertrand, Cournu-Rebeix, Isabelle, Alcina, Antonio, Fedetz, María, Izquierdo, Guillermo, Matesanz, Fuencisla, Hilven, Kelly, Goris, An, Astobiza Pérez, Janire, Alloza Moral, Iraide, Rodríguez-Antigüedad Zarranz, Alfredo, Vandenbroeck, Koen, Akkad, Denis A., Aktas, Orhan, Blaschke, Paul, Buttmann, Mathias, Chan, Andrew, Epplen, Joerg T., Gerdes, Lisa-Ann, Kroner, Antje, Kubisch, Christian, Kümpfel, Tania, Lohse, Peter, Rieckmann, Peter, Zettl, Uwe K., Zipp, Frauke, Bertram, Lars, Lill, Christina M., Fernández, Óscar, Urbaneja, Patricia, Leyva, Laura, Alvarez-Cermeño, José Carlos, Arroyo, Rafael, Garagorri, Aroa M., García-Martínez, Angel, Villar, Luisa M., Urcelay, Elena, Malhotra, Sunny, Montalbán, Xavier, Comabella, Manuel, Berger, Thomas, Fazekas, Franz, Reindl, Markus, Schmied, Mascha C., Zimprich, Alexander, Vilariño-Güell, Carles, Medicina, Neurociencias, Medikuntza, Neurozientziak, Sadovnick, A. Dessa, Traboulsee, Anthony L., Bernales, Cecily Q., Ross, Jay P., Forwell, Amanda L., Yee, Irene M., Guillot-Noel, Lena, Fontaine, Bertrand, Cournu-Rebeix, Isabelle, Alcina, Antonio, Fedetz, María, Izquierdo, Guillermo, Matesanz, Fuencisla, Hilven, Kelly, Goris, An, Astobiza Pérez, Janire, Alloza Moral, Iraide, Rodríguez-Antigüedad Zarranz, Alfredo, Vandenbroeck, Koen, Akkad, Denis A., Aktas, Orhan, Blaschke, Paul, Buttmann, Mathias, Chan, Andrew, Epplen, Joerg T., Gerdes, Lisa-Ann, Kroner, Antje, Kubisch, Christian, Kümpfel, Tania, Lohse, Peter, Rieckmann, Peter, Zettl, Uwe K., Zipp, Frauke, Bertram, Lars, Lill, Christina M., Fernández, Óscar, Urbaneja, Patricia, Leyva, Laura, Alvarez-Cermeño, José Carlos, Arroyo, Rafael, Garagorri, Aroa M., García-Martínez, Angel, Villar, Luisa M., Urcelay, Elena, Malhotra, Sunny, Montalbán, Xavier, Comabella, Manuel, Berger, Thomas, Fazekas, Franz, Reindl, Markus, Schmied, Mascha C., Zimprich, Alexander, and Vilariño-Güell, Carles

Abstract

Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p. G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.931.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.

Published
2016

212. Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology

Author

University of Helsinki, Clinicum, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Eising, Else, Huisman, Sjoerd M. H., Mahfouz, Ahmed, Vijfhuizen, Lisanne S., Anttila, Verneri, Winsvold, Bendik S., Kurth, Tobias, Ikram, M. Arfan, Freilinger, Tobias, Kaprio, Jaakko, Boomsma, Dorret I., van Duijn, Cornelia M., Jarvelin, Marjo-Riitta R., Zwart, John-Anker, Quaye, Lydia, Strachan, David P., Kubisch, Christian, Dichgans, Martin, Smith, George Davey, Stefansson, Kari, Palotie, Aarno, Chasman, Daniel I., Ferrari, Michel D., Terwindt, Gisela M., de Vries, Boukje, Nyholt, Dale R., Lelieveldt, Boudewijn P. F., van den Maagdenberg, Arn M. J. M., Reinders, Marcel J. T., University of Helsinki, Clinicum, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Eising, Else, Huisman, Sjoerd M. H., Mahfouz, Ahmed, Vijfhuizen, Lisanne S., Anttila, Verneri, Winsvold, Bendik S., Kurth, Tobias, Ikram, M. Arfan, Freilinger, Tobias, Kaprio, Jaakko, Boomsma, Dorret I., van Duijn, Cornelia M., Jarvelin, Marjo-Riitta R., Zwart, John-Anker, Quaye, Lydia, Strachan, David P., Kubisch, Christian, Dichgans, Martin, Smith, George Davey, Stefansson, Kari, Palotie, Aarno, Chasman, Daniel I., Ferrari, Michel D., Terwindt, Gisela M., de Vries, Boukje, Nyholt, Dale R., Lelieveldt, Boudewijn P. F., van den Maagdenberg, Arn M. J. M., and Reinders, Marcel J. T.

Abstract

Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.

Published
2016

213. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Author

Gormley, Padhraig, Anttila, Verneri, Winsvold, Bendik S., Palta, Priit, Esko, Tonu, Pers, Tune H., Farh, Kai How, Cuenca-Leon, Ester, Muona, Mikko, Furlotte, Nicholas A., Kurth, Tobias, Ingason, Andres, McMahon, George, Ligthart, Lannie, Terwindt, Gisela M., Kallela, Mikko, Freilinger, Tobias M., Ran, Caroline, Gordon, Scott G., Stam, Anine H., Steinberg, Stacy, Borck, Guntram, Koiranen, Markku, Quaye, Lydia, Adams, Hieab H.H., Lehtimäki, Terho, Sarin, Antti Pekka, Wedenoja, Juho, Hinds, David A., Buring, Julie E., Schürks, Markus, Ridker, Paul M., Hrafnsdottir, Maria Gudlaug, Stefansson, Hreinn, Ring, Susan M., Hottenga, Jouke Jan, Penninx, Brenda W.J.H., Färkkilä, Markus, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Malik, Rainer, Heath, Andrew C., Madden, Pamela A.F., Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja, Kals, Mart, Mägi, Reedik, Pärn, Kalle, Hamalainen, Eija, Huang, Hailiang, Byrnes, Andrea E., Franke, Lude, Huang, Jie, Stergiakouli, Evie, Lee, Phil H., Sandor, Cynthia, Webber, Caleb, Cader, Zameel, Muller-Myhsok, Bertram, Schreiber, Stefan, Meitinger, Thomas, Eriksson, Johan G., Salomaa, Veikko, Heikkilä, Kauko, Loehrer, Elizabeth, Uitterlinden, Andre G., Hofman, Albert, van Duijn, Cornelia, Cherkas, Lynn, Pedersen, Linda M., Stubhaug, Audun, Nielsen, Christopher S., Männikkö, Minna, Mihailov, Evelin, Milani, Lili, Göbel, Hartmut, Esserlind, Ann Louise, Christensen, Anne Francke, Hansen, Thomas Folkmann, Werge, Thomas, Kaprio, Jaakko, Aromaa, Arpo J., Raitakari, Olli, Ikram, M. Arfan, Spector, Tim, Järvelin, Marjo Riitta, Metspalu, Andres, Kubisch, Christian, Strachan, David P., Ferrari, Michel, Belin, Andrea Carmine, Dichgans, Martin, Wessman, Maija, van den Maagdenberg, Arn M.J.M., Zwart, John Anker, Boomsma, Dorret I., Smith, George Davey, Stefansson, Kari, Eriksson, Nicholas, Daly, Mark J., Neale, Benjamin M., Olesen, Jes, Chasman, Daniel I., Nyholt, Dale R., Palotie, Aarno, Børte, Sigrid, Cormand, Bru, Eising, Else, Frants, Rune R., Griffiths, Lyn, Hiekkala, Marjo, Kajanne, Risto, Launer, Lenore, Lehtimaki, Terho, Lessel, Davor, Litterman, Nadia, Macaya, Alfons, Mangino, Massimo, Northover, Carrie, Pedersen, Nancy, Posthuma, Danielle, Pozo-Rosich, Patricia, Pressman, Alice, Sintas, Celia, Strachan, David, Vila-Pueyo, Marta, Wrenthal, William, Zhao, Huiying, other, and, Gormley, Padhraig, Anttila, Verneri, Winsvold, Bendik S., Palta, Priit, Esko, Tonu, Pers, Tune H., Farh, Kai How, Cuenca-Leon, Ester, Muona, Mikko, Furlotte, Nicholas A., Kurth, Tobias, Ingason, Andres, McMahon, George, Ligthart, Lannie, Terwindt, Gisela M., Kallela, Mikko, Freilinger, Tobias M., Ran, Caroline, Gordon, Scott G., Stam, Anine H., Steinberg, Stacy, Borck, Guntram, Koiranen, Markku, Quaye, Lydia, Adams, Hieab H.H., Lehtimäki, Terho, Sarin, Antti Pekka, Wedenoja, Juho, Hinds, David A., Buring, Julie E., Schürks, Markus, Ridker, Paul M., Hrafnsdottir, Maria Gudlaug, Stefansson, Hreinn, Ring, Susan M., Hottenga, Jouke Jan, Penninx, Brenda W.J.H., Färkkilä, Markus, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Malik, Rainer, Heath, Andrew C., Madden, Pamela A.F., Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja, Kals, Mart, Mägi, Reedik, Pärn, Kalle, Hamalainen, Eija, Huang, Hailiang, Byrnes, Andrea E., Franke, Lude, Huang, Jie, Stergiakouli, Evie, Lee, Phil H., Sandor, Cynthia, Webber, Caleb, Cader, Zameel, Muller-Myhsok, Bertram, Schreiber, Stefan, Meitinger, Thomas, Eriksson, Johan G., Salomaa, Veikko, Heikkilä, Kauko, Loehrer, Elizabeth, Uitterlinden, Andre G., Hofman, Albert, van Duijn, Cornelia, Cherkas, Lynn, Pedersen, Linda M., Stubhaug, Audun, Nielsen, Christopher S., Männikkö, Minna, Mihailov, Evelin, Milani, Lili, Göbel, Hartmut, Esserlind, Ann Louise, Christensen, Anne Francke, Hansen, Thomas Folkmann, Werge, Thomas, Kaprio, Jaakko, Aromaa, Arpo J., Raitakari, Olli, Ikram, M. Arfan, Spector, Tim, Järvelin, Marjo Riitta, Metspalu, Andres, Kubisch, Christian, Strachan, David P., Ferrari, Michel, Belin, Andrea Carmine, Dichgans, Martin, Wessman, Maija, van den Maagdenberg, Arn M.J.M., Zwart, John Anker, Boomsma, Dorret I., Smith, George Davey, Stefansson, Kari, Eriksson, Nicholas, Daly, Mark J., Neale, Benjamin M., Olesen, Jes, Chasman, Daniel I., Nyholt, Dale R., Palotie, Aarno, Børte, Sigrid, Cormand, Bru, Eising, Else, Frants, Rune R., Griffiths, Lyn, Hiekkala, Marjo, Kajanne, Risto, Launer, Lenore, Lehtimaki, Terho, Lessel, Davor, Litterman, Nadia, Macaya, Alfons, Mangino, Massimo, Northover, Carrie, Pedersen, Nancy, Posthuma, Danielle, Pozo-Rosich, Patricia, Pressman, Alice, Sintas, Celia, Strachan, David, Vila-Pueyo, Marta, Wrenthal, William, Zhao, Huiying, and other, and

Abstract

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10-8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Published
2016

214. Identification of two novel ALS2 mutations in infantile-onset ascending hereditary spastic paraplegia

Author

Daud, Shakeela, Kakar, Naseebullah, Goebel, Ingrid, Hashmi, Abu Saeed, Yaqub, Tahir, Nuernberg, Gudrun, Nuernberg, Peter, Morris-Rosendahl, Deborah J., Wasim, Muhammad, Volk, Alexander E., Kubisch, Christian, Ahmad, Jainil, Borck, Guntram, Daud, Shakeela, Kakar, Naseebullah, Goebel, Ingrid, Hashmi, Abu Saeed, Yaqub, Tahir, Nuernberg, Gudrun, Nuernberg, Peter, Morris-Rosendahl, Deborah J., Wasim, Muhammad, Volk, Alexander E., Kubisch, Christian, Ahmad, Jainil, and Borck, Guntram

Abstract

Biallelic mutations of ALS2 cause a clinical spectrum of overlapping autosomal recessive neurodegenerative disorders: infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (ALS2). We report on eleven individuals affected with IAHSP from two consanguineous Pakistani families. A combination of linkage analysis with homozygosity mapping and targeted sequencing identified two novel ALS2 mutations, a c.194T>C (p.Phe65Ser) missense substitution located in the first RCC-like domain of ALS2/alsin and a c.2998delA (p.Ile1000*) nonsense mutation. This study of extended families including a total of eleven affected individuals suggests that a given ALS2 mutation may lead to a phenotype with remarkable intrafamilial clinical homogeneity.

Published
2016

215. Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.

Author

Spielmann, Malte, Spielmann, Malte, Kakar, Naseebullah, Tayebi, Naeimeh, Leettola, Catherine, Nürnberg, Gudrun, Sowada, Nadine, Lupiáñez, Darío G, Harabula, Izabela, Flöttmann, Ricarda, Horn, Denise, Chan, Wing Lee, Wittler, Lars, Yilmaz, Rüstem, Altmüller, Janine, Thiele, Holger, van Bokhoven, Hans, Schwartz, Charles E, Nürnberg, Peter, Bowie, James U, Ahmad, Jamil, Kubisch, Christian, Mundlos, Stefan, Borck, Guntram, Spielmann, Malte, Spielmann, Malte, Kakar, Naseebullah, Tayebi, Naeimeh, Leettola, Catherine, Nürnberg, Gudrun, Sowada, Nadine, Lupiáñez, Darío G, Harabula, Izabela, Flöttmann, Ricarda, Horn, Denise, Chan, Wing Lee, Wittler, Lars, Yilmaz, Rüstem, Altmüller, Janine, Thiele, Holger, van Bokhoven, Hans, Schwartz, Charles E, Nürnberg, Peter, Bowie, James U, Ahmad, Jamil, Kubisch, Christian, Mundlos, Stefan, and Borck, Guntram

Abstract

The CRISPR/Cas technology enables targeted genome editing and the rapid generation of transgenic animal models for the study of human genetic disorders. Here we describe an autosomal recessive human disease in two unrelated families characterized by a split-foot defect, nail abnormalities of the hands, and hearing loss, due to mutations disrupting the SAM domain of the protein kinase ZAK. ZAK is a member of the MAPKKK family with no known role in limb development. We show that Zak is expressed in the developing limbs and that a CRISPR/Cas-mediated knockout of the two Zak isoforms is embryonically lethal in mice. In contrast, a deletion of the SAM domain induces a complex hindlimb defect associated with down-regulation of Trp63, a known split-hand/split-foot malformation disease gene. Our results identify ZAK as a key player in mammalian limb patterning and demonstrate the rapid utility of CRISPR/Cas genome editing to assign causality to human mutations in the mouse in <10 wk.

Published
2016

217. WRNMutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects

Author

Yokote, Koutaro, primary, Chanprasert, Sirisak, additional, Lee, Lin, additional, Eirich, Katharina, additional, Takemoto, Minoru, additional, Watanabe, Aki, additional, Koizumi, Naoko, additional, Lessel, Davor, additional, Mori, Takayasu, additional, Hisama, Fuki M., additional, Ladd, Paula D., additional, Angle, Brad, additional, Baris, Hagit, additional, Cefle, Kivanc, additional, Palanduz, Sukru, additional, Ozturk, Sukru, additional, Chateau, Antoinette, additional, Deguchi, Kentaro, additional, Easwar, T.K.M, additional, Federico, Antonio, additional, Fox, Amy, additional, Grebe, Theresa A., additional, Hay, Beverly, additional, Nampoothiri, Sheela, additional, Seiter, Karen, additional, Streeten, Elizabeth, additional, Piña-Aguilar, Raul E., additional, Poke, Gemma, additional, Poot, Martin, additional, Posmyk, Renata, additional, Martin, George M., additional, Kubisch, Christian, additional, Schindler, Detlev, additional, and Oshima, Junko, additional

Published
2016
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220. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients

Author

Sadovnick, A Dessa, primary, Traboulsee, Anthony L, additional, Bernales, Cecily Q, additional, Ross, Jay P, additional, Forwell, Amanda L, additional, Yee, Irene M, additional, Guillot-Noel, Lena, additional, Fontaine, Bertrand, additional, Cournu-Rebeix, Isabelle, additional, Alcina, Antonio, additional, Fedetz, Maria, additional, Izquierdo, Guillermo, additional, Matesanz, Fuencisla, additional, Hilven, Kelly, additional, Dubois, Bénédicte, additional, Goris, An, additional, Astobiza, Ianire, additional, Alloza, Iraide, additional, Antigüedad, Alfredo, additional, Vandenbroeck, Koen, additional, Akkad, Denis A, additional, Aktas, Orhan, additional, Blaschke, Paul, additional, Buttmann, Mathias, additional, Chan, Andrew, additional, Epplen, Joerg T, additional, Gerdes, Lisa-Ann, additional, Kroner, Antje, additional, Kubisch, Christian, additional, Kümpfel, Tania, additional, Lohse, Peter, additional, Rieckmann, Peter, additional, Zettl, Uwe K, additional, Zipp, Frauke, additional, Bertram, Lars, additional, Lill, Christina M, additional, Fernandez, Oscar, additional, Urbaneja, Patricia, additional, Leyva, Laura, additional, Alvarez-Cermeño, Jose Carlos, additional, Arroyo, Rafael, additional, Garagorri, Aroa M, additional, García-Martínez, Angel, additional, Villar, Luisa M, additional, Urcelay, Elena, additional, Malhotra, Sunny, additional, Montalban, Xavier, additional, Comabella, Manuel, additional, Berger, Thomas, additional, Fazekas, Franz, additional, Reindl, Markus, additional, Schmied, Mascha C, additional, Zimprich, Alexander, additional, and Vilariño-Güell, Carles, additional

Published
2016
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221. Gene co-expression analysis identifies brain regions and cell types involved in migraine pathophysiology: a GWAS-based study using the Allen Human Brain Atlas

Author

Eising, Else, primary, Huisman, Sjoerd M. H., additional, Mahfouz, Ahmed, additional, Vijfhuizen, Lisanne S., additional, Anttila, Verneri, additional, Winsvold, Bendik S., additional, Kurth, Tobias, additional, Ikram, M. Arfan, additional, Freilinger, Tobias, additional, Kaprio, Jaakko, additional, Boomsma, Dorret I., additional, van Duijn, Cornelia M., additional, Järvelin, Marjo-Riitta R., additional, Zwart, John-Anker, additional, Quaye, Lydia, additional, Strachan, David P., additional, Kubisch, Christian, additional, Dichgans, Martin, additional, Davey Smith, George, additional, Stefansson, Kari, additional, Palotie, Aarno, additional, Chasman, Daniel I., additional, Ferrari, Michel D., additional, Terwindt, Gisela M., additional, de Vries, Boukje, additional, Nyholt, Dale R., additional, Lelieveldt, Boudewijn P. F., additional, van den Maagdenberg, Arn M. J. M., additional, and Reinders, Marcel J. T., additional

Published
2016
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222. Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice

Author

Spielmann, Malte, primary, Kakar, Naseebullah, additional, Tayebi, Naeimeh, additional, Leettola, Catherine, additional, Nürnberg, Gudrun, additional, Sowada, Nadine, additional, Lupiáñez, Darío G., additional, Harabula, Izabela, additional, Flöttmann, Ricarda, additional, Horn, Denise, additional, Chan, Wing Lee, additional, Wittler, Lars, additional, Yilmaz, Rüstem, additional, Altmüller, Janine, additional, Thiele, Holger, additional, van Bokhoven, Hans, additional, Schwartz, Charles E., additional, Nürnberg, Peter, additional, Bowie, James U., additional, Ahmad, Jamil, additional, Kubisch, Christian, additional, Mundlos, Stefan, additional, and Borck, Guntram, additional

Published
2016
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223. Identification of two novel ALS2 mutations in infantile-onset ascending hereditary spastic paraplegia

Author

Daud, Shakeela, primary, Kakar, Naseebullah, additional, Goebel, Ingrid, additional, Hashmi, Abu Saeed, additional, Yaqub, Tahir, additional, Nürnberg, Gudrun, additional, Nürnberg, Peter, additional, Morris-Rosendahl, Deborah J., additional, Wasim, Muhammad, additional, Volk, Alexander E., additional, Kubisch, Christian, additional, Ahmad, Jamil, additional, and Borck, Guntram, additional

Published
2016
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224. De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment

Author

Hempel, Maja, Cremer, Kirsten, Ockeloen, Charlotte W., Lichtenbelt, Klaske D., Herkert, Johanna C., Denecke, Jonas, Haack, Tobias B., Zink, Alexander M., Becker, Jessica, Wohlleber, Eva, Johannsen, Jessika, Alhaddad, Bader, Pfundt, Rolph, Fuchs, Sigrid, Wieczorek, Dagmar, Strom, Tim M., Van Gassen, Koen L I, Kleefstra, Tjitske, Kubisch, Christian, Engels, Hartmut, Lessel, Davor, Hempel, Maja, Cremer, Kirsten, Ockeloen, Charlotte W., Lichtenbelt, Klaske D., Herkert, Johanna C., Denecke, Jonas, Haack, Tobias B., Zink, Alexander M., Becker, Jessica, Wohlleber, Eva, Johannsen, Jessika, Alhaddad, Bader, Pfundt, Rolph, Fuchs, Sigrid, Wieczorek, Dagmar, Strom, Tim M., Van Gassen, Koen L I, Kleefstra, Tjitske, Kubisch, Christian, Engels, Hartmut, and Lessel, Davor

Published
2015

225. STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly

Author

Kakar, Naseebullah, Ahmad, Jamil, Morris-Rosendahl, Deborah J., Altmueller, Janine, Friedrich, Katrin, Barbi, Gotthold, Nuernberg, Peter, Kubisch, Christian, Dobyns, William B., Borck, Guntram, Kakar, Naseebullah, Ahmad, Jamil, Morris-Rosendahl, Deborah J., Altmueller, Janine, Friedrich, Katrin, Barbi, Gotthold, Nuernberg, Peter, Kubisch, Christian, Dobyns, William B., and Borck, Guntram

Abstract

Holoprosencephaly is a clinically and genetically heterogeneous midline brain malformation associated with neurologic manifestations including developmental delay, intellectual disability and seizures. Although mutations in the sonic hedgehog gene SHH and more than 10 other genes are known to cause holoprosencephaly, many patients remain without a molecular diagnosis. Here we show that a homozygous truncating mutation of STIL not only causes severe autosomal recessive microcephaly, but also lobar holoprosencephaly in an extended consanguineous Pakistani family. STIL mutations have previously been linked to centrosomal defects in primary microcephaly at the MCPH7 locus. Our results thus expand the clinical phenotypes associated with biallellic STIL mutations to include holoprosencephaly.

Published
2015

226. BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies

Author

Borck, Guntram, Hog, Friederike, Dentici, Maria Lisa, Tan, Perciliz L., Sowada, Nadine, Medeira, Ana, Gueneau, Lucie, Thiele, Holger, Kousi, Maria, Lepri, Francesca, Wenzeck, Larissa, Blumenthal, Ian, Radicioni, Antonio, Schwarzenberg, Tito Livio, Mandriani, Barbara, Fischetto, Rita, Morris-Rosendahl, Deborah J., Altmuller, Janine, Reymond, Alexandre, Nurnberg, Peter, Merla, Giuseppe, Dallapiccola, Bruno, Katsanis, Nicholas, Cramer, Patrick, Kubisch, Christian, Borck, Guntram, Hog, Friederike, Dentici, Maria Lisa, Tan, Perciliz L., Sowada, Nadine, Medeira, Ana, Gueneau, Lucie, Thiele, Holger, Kousi, Maria, Lepri, Francesca, Wenzeck, Larissa, Blumenthal, Ian, Radicioni, Antonio, Schwarzenberg, Tito Livio, Mandriani, Barbara, Fischetto, Rita, Morris-Rosendahl, Deborah J., Altmuller, Janine, Reymond, Alexandre, Nurnberg, Peter, Merla, Giuseppe, Dallapiccola, Bruno, Katsanis, Nicholas, Cramer, Patrick, and Kubisch, Christian

Abstract

RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of bif1 in zebraflsh embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III-related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development.

Published
2015

227. Exome sequencing identifies a novel heterozygous TGFB3 mutation in a disorder overlapping with Marfan and Loeys-Dietz syndrome

Author

Kuechler, Alma, Altmueller, Janine, Nuernberg, Peter, Kotthoff, Stefan, Kubisch, Christian, Borck, Guntram, Kuechler, Alma, Altmueller, Janine, Nuernberg, Peter, Kotthoff, Stefan, Kubisch, Christian, and Borck, Guntram

Abstract

Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are clinically related autosomal dominant systemic connective tissue disorders. Although mutations in several genes of the TGF-beta signalling and related pathways have been identified in the past (e.g. FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2), there are still many individuals with marfanoid phenotypes in whom no causative mutations are identified. We performed whole exome sequencing in two of three affected individuals from a family with phenotypic features overlapping MFS and LDS. The two affected children and their affected father had tall stature, arachnodactyly, hyperextensible joints, hypertelorism, bifid uvula, but no cardiac involvement, aortic dilation or eye involvement. We detected a novel heterozygous mutation in TGFB3, c.898C>G, predicting the missense substitution p.Arg300Gly. Sanger sequencing confirmed the mutation and its segregation with the phenotype. The first two TGFB3 mutations were reported previously in two unrelated individuals with marfanoid features: one individual with growth retardation carried a heterozygous loss-of-function mutation (c.1226G>A; p.Cys409Tyr; Rienhoff et al., 2013), whereas a child with overgrowth carried a mutation in the same codon as the mutation identified in the three affected individuals reported here (c.899G>A; p.Arg300Gln; Matyas et al., 2014). The mutations at codon Arg300 presumably lead to increased TGF-beta signalling, suggesting that the short or tall stature seen in patients with TGFB3 mutations may result from opposing effects of mutations on TGF-beta signalling. Thus, we add a novel human TGFB3 mutation, contribute to the clinical delineation of the emerging connective tissue disorder tentatively called Rienhoff syndrome and compare the data with a very recent report (Bertoli-Avella et al., 2015) on TGFB3 mutations associated with aortic aneurysms or dissections. (C) 2015 Elsevier Ltd. All rights reserved.

Published
2015

228. De novo FUS mutations are the most frequent genetic cause in early-onset German ALS patients

Author

Huebers, Annemarie, Just, Walter, Rosenbohm, Angela, Mueller, Kathrin, Marroquin, Nicolai, Goebel, Ingrid, Hoegel, Josef, Thiele, Holger, Altmueller, Janine, Nuernberg, Peter, Weishaupt, Jochen H., Kubisch, Christian, Ludolph, Albert C., Volk, Alexander E., Huebers, Annemarie, Just, Walter, Rosenbohm, Angela, Mueller, Kathrin, Marroquin, Nicolai, Goebel, Ingrid, Hoegel, Josef, Thiele, Holger, Altmueller, Janine, Nuernberg, Peter, Weishaupt, Jochen H., Kubisch, Christian, Ludolph, Albert C., and Volk, Alexander E.

Abstract

In amyotrophic lateral sclerosis (ALS) patients with known genetic cause, mutations in chromosome 9 open reading frame 72 (C9orf72) and superoxide dismutase 1 (SOD1) account for most familial and late-onset sporadic cases, whereas mutations in fused in sarcoma (FUS) can be identified in just around 5% of familial and 1% of overall sporadic cases. There are only few reports on de novo FUS mutations in juvenile ALS patients. To date, no systematic evaluation on the frequency of de novo FUS mutations in early-onset ALS patients has been conducted. Here, we screened a cohort of 14 early-onset sporadic ALS patients (onset age <35 years) to determine the frequency of mutations in C9orf72, SOD1, and FUS in this defined patient cohort. All patients were recruited prospectively by a single center in a period of 38 months. No mutations were detected in SOD1 or C9orf72; however, we identified 6 individuals (43%) carrying a heterozygous FUS mutation including 1 mutation that has not been described earlier (c.1504delG [p.Asp502Thrfs*27]). Genetic testing of parents was possible in 5 families and revealed that the mutations in these patients arose de novo. Three of the 6 identified patients presented with initial bulbar symptoms. Our study identifies FUS mutations as the most frequent genetic cause in early-onset ALS. Genetic testing of FUS thus seems indicated in sporadic early-onset ALS patients especially if showing predominant bulbar symptoms and an aggressive disease course. (C) 2015 Elsevier Inc. All rights reserved.

Published
2015

229. De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment

Author

Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Klinische Genetica, Hempel, Maja, Cremer, Kirsten, Ockeloen, Charlotte W., Lichtenbelt, Klaske D., Herkert, Johanna C., Denecke, Jonas, Haack, Tobias B., Zink, Alexander M., Becker, Jessica, Wohlleber, Eva, Johannsen, Jessika, Alhaddad, Bader, Pfundt, Rolph, Fuchs, Sigrid, Wieczorek, Dagmar, Strom, Tim M., Van Gassen, Koen L I, Kleefstra, Tjitske, Kubisch, Christian, Engels, Hartmut, Lessel, Davor, Genetica Sectie Genoomdiagnostiek, Child Health, Genetica Klinische Genetica, Hempel, Maja, Cremer, Kirsten, Ockeloen, Charlotte W., Lichtenbelt, Klaske D., Herkert, Johanna C., Denecke, Jonas, Haack, Tobias B., Zink, Alexander M., Becker, Jessica, Wohlleber, Eva, Johannsen, Jessika, Alhaddad, Bader, Pfundt, Rolph, Fuchs, Sigrid, Wieczorek, Dagmar, Strom, Tim M., Van Gassen, Koen L I, Kleefstra, Tjitske, Kubisch, Christian, Engels, Hartmut, and Lessel, Davor

Published
2015

230. Current knowledge and recent insights into the genetic basis of amyotrophic lateral sclerosis.

Author

Volk, Alexander E., Weishaupt, Jochen H., Andersen, Peter M., Ludolph, Albert C., and Kubisch, Christian

Abstract

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease, affecting the upper and/or lower motor neurons. However, extramotor symptoms can also occur; cognitive deficits are present in more than 40% of patients and 5-8% of ALS patients develop frontotemporal dementia. There is no effective treatment for ALS and median survival is 2-3 years after onset.Amyotrophic lateral sclerosis is a genetically heterogeneous disorder with monogenic forms as well as complex genetic etiology. Currently, complex genetic risk factors are of minor interest for routine diagnostic testing or counseling of patients and their families. By contrast, a monogenic cause can be identified in 70% of familial and 10% of sporadic ALS cases. The most frequent genetic cause is a noncoding hexanucleotide repeat expansion in the C9orf72 gene. In recent years, high-throughput sequencing technologies have helped to identify additional monogenic and complex risk factors of ALS.Genetic counseling should be offered to all ALS patients and their first- and possibly second-degree relatives, and should include information about the possibilities and limitations of genetic testing. Routine diagnostic testing should at least encompass the most frequently mutated disease genes (C9orf72, SOD1, TDP-43, FUS). Targeted sequencing approaches including further disease genes may be applied. Caution is warranted as the C9orf72 repeat expansion cannot be detected by routine sequencing technologies and testing by polymerase chain reaction (PCR) is failure-prone.Predictive testing is possible in families in which a genetic cause has been identified, but the limitations of genetic testing (i. e., the problems of incomplete penetrance, variable expressivity and possible oligogenic inheritance) have to be explained to the families. [ABSTRACT FROM AUTHOR]

Published
2018
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231. The metabolic and endocrine characteristics in spinal and bulbar muscular atrophy.

Author

Rosenbohm, Angela, Hirsch, Susanne, Volk, Alexander E., Grehl, Torsten, Grosskreutz, Julian, Hanisch, Frank, Herrmann, Andreas, Kollewe, Katja, Kress, Wolfram, Meyer, Thomas, Petri, Susanne, Prudlo, Johannes, Wessig, Carsten, Müller, Hans-Peter, Dreyhaupt, Jens, Weishaupt, Jochen, Kubisch, Christian, Kassubek, Jan, Weydt, Patrick, and Ludolph, Albert C.

Subjects
SPINAL muscular atrophy, ANDROGEN receptors, PHENOTYPES, BIOMARKERS, DEGLUTITION disorders, GYNECOMASTIA, ANDROGEN-insensitivity syndrome, BODY mass index
Abstract

Objective: Spinal and bulbar muscular atrophy (SBMA) is caused by an abnormal expansion of the CAG repeat in the androgen receptor gene. This study aimed to systematically phenotype a German SBMA cohort (n = 80) based on laboratory markers for neuromuscular, metabolic, and endocrine status, and thus provide a basis for the selection of biomarkers for future therapeutic trials.Methods: We assessed a panel of 28 laboratory parameters. The clinical course and blood biomarkers were correlated with disease duration and CAG repeat length. A subset of 11 patients was evaluated with body fat MRI.Results: Almost all patients reported muscle weakness (99%), followed by dysphagia (77%), tremor (76%), and gynecomastia (75%) as major complaints. Creatine kinase was the most consistently elevated (94%) serum marker, which, however, did not relate with either the disease duration or the CAG repeat length. Paresis duration and CAG repeat length correlated with dehydroepiandrosterone sulfate after correction for body mass index and age. The androgen insensitivity index was elevated in nearly half of the participants (48%).Conclusions: Metabolic alterations in glucose homeostasis (diabetes) and fat metabolism (combined hyperlipidemia), and sex hormone abnormalities (androgen insensitivity) could be observed among SBMA patients without association with the neuromuscular phenotype. Dehydroepiandrosterone sulfate was the only biomarker that correlated strongly with both weakness duration and the CAG repeat length after adjusting for age and BMI, indicating its potential as a biomarker for both disease severity and duration and, therefore, its possible use as a reliable outcome measure in future therapeutic studies. [ABSTRACT FROM AUTHOR]

Published
2018
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232. Hot-spot KIF5A mutations cause familial ALS.

Author

Brenner, David, Yilmaz, Rüstem, Müller, Kathrin, Grehl, Torsten, Petri, Susanne, Meyer, Thomas, Grosskreutz, Julian, Weydt, Patrick, Wolfgang Ruf, Neuwirth, Christoph, Weber, Markus, Pinto, Susana, Claeys, Kristl G., Schrank, Berthold, Jordan, Berit, Knehr, Antje, Günther, Kornelia, Hübers, Annemarie, Zeller, Daniel, and Kubisch, Christian

Subjects
MISSENSE mutation, PARAPLEGIA, AXONAL transport, CHARCOT-Marie-Tooth disease, NEURODEVELOPMENTAL treatment, GENETICS, GENETICS of amyotrophic lateral sclerosis, ADENOSINE triphosphatase, ALLELES, AMYOTROPHIC lateral sclerosis, BIOLOGICAL transport, GENE expression, GENOMES, GENETIC mutation, FAMILIAL spastic paraplegia
Abstract

Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 × 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p.Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 × 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis. [ABSTRACT FROM AUTHOR]

Published
2018
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233. Expanding the phenotype associated with biallelic <italic>WDR60</italic> mutations: Siblings with retinal degeneration and polydactyly lacking other features of short rib thoracic dystrophies.

Author

Kakar, Naseebullah, Horn, Denise, Decker, Eva, Sowada, Nadine, Kubisch, Christian, Ahmad, Jamil, Borck, Guntram, and Bergmann, Carsten

Abstract

Ciliopathies are disorders of the primary cilium that can affect almost all organs and that are characterized by pleiotropy and extensive intra‐ and interfamilial phenotypic variability. Accordingly, mutations in the same gene can cause different ciliopathy phenotypes of varying severity. WDR60 encodes a protein thought to play a role in the primary cilium's intraflagellar transport machinery. Mutations in this gene are a rare cause of Jeune asphyxiating thoracic dystrophy (JATD) and short‐rib polydactyly syndrome (SRPS). Here we report on a milder and distinct phenotype in a consanguineous Pakistani pedigree with two adolescent sisters affected by retinal degeneration and postaxial polydactyly, but lack of any further skeletal or chondrodysplasia features. By targeted high‐throughput sequencing of genes known or suspected to be involved in ciliogenesis, we detected a novel homozygous N‐terminal truncating WDR60 mutation (c.44delC/p.Ala15Glufs*90) that co‐segregated with the disease in the family. Our finding broadens the spectrum of WDR60‐related phenotypes and shows the utility of broad multigene panels during the genetic work‐up of patients with ciliopathies. [ABSTRACT FROM AUTHOR]

Published
2018
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234. Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors

Author

AlDubayan, Saud H., Pyle, Louise C., Gamulin, Marija, Kulis, Tomislav, Moore, Nathanael D., Taylor-Weiner, Amaro, Hamid, Anis A., Reardon, Brendan, Wubbenhorst, Bradley, Godse, Rama, Vaughn, David J., Jacobs, Linda A., Meien, Stefanie, Grgic, Mislav, Kastelan, Zeljko, Markt, Sarah C., Damrauer, Scott M., Rader, Daniel J., Kember, Rachel L., Loud, Jennifer T., Kanetsky, Peter A., Greene, Mark H., Sweeney, Christopher J., Kubisch, Christian, Nathanson, Katherine L., Van Allen, Eliezer M., Stewart, Douglas R., and Lessel, Davor

Abstract

IMPORTANCE: Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs. OBJECTIVE: To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls. DESIGN, SETTING, AND PARTICIPANTS: A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018. MAIN OUTCOMES AND MEASURES: Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls. RESULTS: Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009). CONCLUSIONS AND RELEVANCE: This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.

Published
2019
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236. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Author

Gormley, Padhraig, primary, Anttila, Verneri, additional, Winsvold, Bendik S, additional, Palta, Priit, additional, Esko, Tonu, additional, Pers, Tune H, additional, Farh, Kai-How, additional, Cuenca-Leon, Ester, additional, Muona, Mikko, additional, Furlotte, Nicholas A, additional, Kurth, Tobias, additional, Ingason, Andres, additional, McMahon, George, additional, Ligthart, Lannie, additional, Terwindt, Gisela M, additional, Kallela, Mikko, additional, Freilinger, Tobias M, additional, Ran, Caroline, additional, Gordon, Scott G, additional, Stam, Anine H, additional, Steinberg, Stacy, additional, Borck, Guntram, additional, Koiranen, Markku, additional, Quaye, Lydia, additional, Adams, Hieab HH, additional, Lehtimaki, Terho, additional, Sarin, Antti-Pekka, additional, Wedenoja, Juho, additional, Hinds, David A, additional, Buring, Julie E, additional, Schurks, Markus, additional, Ridker, Paul M, additional, Hrafnsdottir, Maria Gudlaug, additional, Stefansson, Hreinn, additional, Ring, Susan M, additional, Hottenga, Jouke-Jan, additional, Penninx, Brenda WJH, additional, Farkkila, Markus, additional, Artto, Ville, additional, Kaunisto, Mari, additional, Vepsalainen, Salli, additional, Malik, Rainer, additional, Heath, Andrew C, additional, Madden, Pamela AF, additional, Martin, Nicholas G, additional, Montgomery, Grant W, additional, Hamalainen, Eija, additional, Huang, Hailiang, additional, Byrnes, Andrea E, additional, Franke, Lude, additional, Huang, Jie, additional, Stergiakouli, Evie, additional, Lee, Phil H, additional, Sandor, Cynthia, additional, Webber, Caleb, additional, Cader, Zameel, additional, Muller-Myhsok, Bertram, additional, Schreiber, Stefan, additional, Meitinger, Thomas, additional, Eriksson, Johan G, additional, Salomaa, Veikko, additional, Heikkila, Kauko, additional, Loehrer, Elizabeth, additional, Uitterlinden, Andre G, additional, Hofman, Albert, additional, van Duijn, Cornelia M, additional, Cherkas, Lynn, additional, Pedersen, Linda M, additional, Stubhaug, Audun, additional, Nielsen, Christopher S, additional, Mannikko, Minna, additional, Mihailov, Evelin, additional, Milani, Lili, additional, Gobel, Hartmut, additional, Esserlind, Ann-Louise, additional, Christensen, Anne Francke, additional, Hansen, Thomas Folkmann, additional, Werge, Thomas, additional, Kaprio, Jaakko, additional, Aromaa, Arpo J, additional, Raitakari, Olli, additional, Ikram, M Arfan, additional, Spector, Tim, additional, Jarvelin, Marjo-Riitta, additional, Metspalu, Andres, additional, Kubisch, Christian, additional, Strachan, David P, additional, Ferrari, Michel D, additional, Belin, Andrea C, additional, Dichgans, Martin, additional, Wessman, Maija, additional, van den Maagdenberg, Arn MJM, additional, Zwart, John-Anker, additional, Boomsma, Dorret I, additional, Smith, George Davey, additional, Stefansson, Kari, additional, Eriksson, Nicholas, additional, Daly, Mark J, additional, Neale, Benjamin M, additional, Olesen, Jes, additional, Chasman, Daniel I, additional, Nyholt, Dale R, additional, and Palotie, Aarno, additional

Published
2015
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237. De novo FUS mutations are the most frequent genetic cause in early-onset German ALS patients

Author

Hübers, Annemarie, primary, Just, Walter, additional, Rosenbohm, Angela, additional, Müller, Kathrin, additional, Marroquin, Nicolai, additional, Goebel, Ingrid, additional, Högel, Josef, additional, Thiele, Holger, additional, Altmüller, Janine, additional, Nürnberg, Peter, additional, Weishaupt, Jochen H., additional, Kubisch, Christian, additional, Ludolph, Albert C., additional, and Volk, Alexander E., additional

Published
2015
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238. Genome-wide significant association with seven novel multiple sclerosis risk loci

Author

Lill, Christina M, primary, Luessi, Felix, additional, Alcina, Antonio, additional, Sokolova, Ekaterina A, additional, Ugidos, Nerea, additional, de la Hera, Belén, additional, Guillot-Noël, Léna, additional, Malhotra, Sunny, additional, Reinthaler, Eva, additional, Schjeide, Brit-Maren M, additional, Mescheriakova, Julia Y, additional, Mashychev, Andriy, additional, Wohlers, Inken, additional, Akkad, Denis A, additional, Aktas, Orhan, additional, Alloza, Iraide, additional, Antigüedad, Alfredo, additional, Arroyo, Rafa, additional, Astobiza, Ianire, additional, Blaschke, Paul, additional, Boyko, Alexei N, additional, Buttmann, Mathias, additional, Chan, Andrew, additional, Dörner, Thomas, additional, Epplen, Joerg T, additional, Favorova, Olga O, additional, Fedetz, Maria, additional, Fernández, Oscar, additional, García-Martínez, Angel, additional, Gerdes, Lisa-Ann, additional, Graetz, Christiane, additional, Hartung, Hans-Peter, additional, Hoffjan, Sabine, additional, Izquierdo, Guillermo, additional, Korobko, Denis S, additional, Kroner, Antje, additional, Kubisch, Christian, additional, Kümpfel, Tania, additional, Leyva, Laura, additional, Lohse, Peter, additional, Malkova, Nadezhda A, additional, Montalban, Xavier, additional, Popova, Ekaterina V, additional, Rieckmann, Peter, additional, Rozhdestvenskii, Alexei S, additional, Schmied, Christiane, additional, Smagina, Inna V, additional, Tsareva, Ekaterina Y, additional, Winkelmann, Alexander, additional, Zettl, Uwe K, additional, Binder, Harald, additional, Cournu-Rebeix, Isabelle, additional, Hintzen, Rogier, additional, Zimprich, Alexander, additional, Comabella, Manuel, additional, Fontaine, Bertrand, additional, Urcelay, Elena, additional, Vandenbroeck, Koen, additional, Filipenko, Maxim, additional, Matesanz, Fuencisla, additional, Zipp, Frauke, additional, and Bertram, Lars, additional

Published
2015
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241. De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment

Author

Hempel, Maja, primary, Cremer, Kirsten, additional, Ockeloen, Charlotte W., additional, Lichtenbelt, Klaske D., additional, Herkert, Johanna C., additional, Denecke, Jonas, additional, Haack, Tobias B., additional, Zink, Alexander M., additional, Becker, Jessica, additional, Wohlleber, Eva, additional, Johannsen, Jessika, additional, Alhaddad, Bader, additional, Pfundt, Rolph, additional, Fuchs, Sigrid, additional, Wieczorek, Dagmar, additional, Strom, Tim M., additional, van Gassen, Koen L.I., additional, Kleefstra, Tjitske, additional, Kubisch, Christian, additional, Engels, Hartmut, additional, and Lessel, Davor, additional

Published
2015
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242. Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients

Author

Steinacker, Petra, primary, Feneberg, Emily, additional, Weishaupt, Jochen, additional, Brettschneider, Johannes, additional, Tumani, Hayrettin, additional, Andersen, Peter M, additional, von Arnim, Christine A F, additional, Böhm, Sarah, additional, Kassubek, Jan, additional, Kubisch, Christian, additional, Lulé, Dorothée, additional, Müller, Hans-Peter, additional, Muche, Rainer, additional, Pinkhardt, Elmar, additional, Oeckl, Patrick, additional, Rosenbohm, Angela, additional, Anderl-Straub, Sarah, additional, Volk, Alexander E, additional, Weydt, Patrick, additional, Ludolph, Albert C, additional, and Otto, Markus, additional

Published
2015
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243. POLD1Germline Mutations in Patients Initially Diagnosed with Werner Syndrome

Author

Lessel, Davor, primary, Hisama, Fuki M., additional, Szakszon, Katalin, additional, Saha, Bidisha, additional, Sanjuanelo, Alexander Barrios, additional, Salbert, Bonnie A., additional, Steele, Pamela D., additional, Baldwin, Jennifer, additional, Brown, W. Ted, additional, Piussan, Charles, additional, Plauchu, Henri, additional, Szilvássy, Judit, additional, Horkay, Edit, additional, Högel, Josef, additional, Martin, George M., additional, Herr, Alan J., additional, Oshima, Junko, additional, and Kubisch, Christian, additional

Published
2015
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246. Genome wide association study identifies variants in NBEA associated with migraine in bipolar disorder

Author

Jacobsen, Kaya K., primary, Nievergelt, Caroline M., additional, Zayats, Tetyana, additional, Greenwood, Tiffany A., additional, Anttila, Verneri, additional, Akiskal, Hagop S., additional, Haavik, Jan, additional, Bernt Fasmer, Ole, additional, Kelsoe, John R., additional, Johansson, Stefan, additional, Oedegaard, Ketil J., additional, McKinney, Rebecca, additional, Shilling, Paul D., additional, Smith, Erin N., additional, Schork, Nicholas J., additional, Bloss, Cinnamon S., additional, Nurnberger, John I., additional, Edenberg, Howard J., additional, Foroud, Tatiana, additional, Koller, Daniel L., additional, Gershon, Elliot S., additional, Badner, Judith A., additional, Liu, Chunyu, additional, Scheftner, William A., additional, Lawson, William B., additional, Nwulia, Evaristus A., additional, Hipolito, Maria, additional, Potash, James, additional, Coryell, William, additional, Rice, John, additional, Byerley, William, additional, McMahon, Francis J., additional, Berrettini, Wade H., additional, Zandi, Peter P., additional, Mahon, Pamela B., additional, McInnis, Melvin G., additional, Zöllner, Sebastian, additional, Zhang, Peng, additional, Craig, David W., additional, Szelinger, Szabolics, additional, Barrett, Thomas B., additional, Schulze, Thomas G., additional, Wedenoja, Juho, additional, Kaunisto, Mari A., additional, Heikkilä, Kauko, additional, Kaprio, Jaakko, additional, Wessman, Maija, additional, Kallela, Mikko, additional, Färkkilä, Markus, additional, Artto, Ville, additional, Aromaa, Arpo, additional, Eriksson, Johan G., additional, Winsvold, Bendik S., additional, Zwart, John-Anker, additional, Gormley, Padhraig, additional, Palotie, Aarno, additional, Kurth, Tobias, additional, Rose, Lynda M., additional, Buring, Julie E., additional, Ridker, Paul M., additional, Chasman, Daniel I., additional, Bettella, Francesco, additional, Steinberg, Stacy, additional, Stefansson, Hreinn, additional, Stefansson, Kari, additional, McMahon, George, additional, Davey-Smith, George, additional, Malik, Rainer, additional, Freilinger, Tobias, additional, Erich Wichmann, Heinz, additional, Dichgans, Martin, additional, Muller-Myhsok, Bertram, additional, Meitinger, Thomas, additional, de Vries, Boukje, additional, Terwindt, Gisela, additional, Stam, Anine H., additional, Frants, Rune R., additional, Pelzer, Nadine, additional, Weller, Claudia M., additional, Zielman, Ronald, additional, Ferrari, Michel D., additional, van den Maagdenberg, Arn M.J.M., additional, Medland, Sarah E., additional, Montgomery, Grant W., additional, Martin, Nicholas G., additional, Nyholt, Dale R., additional, Todt, Unda, additional, Borck, Guntram, additional, Kubisch, Christian, additional, Quaye, Lydia, additional, Williams, Frances M.K., additional, Cherkas, Lynn, additional, Koiranen, Markku, additional, Hartikainen, Anna-Liisa, additional, Pouta, Anneli, additional, Jarvelin, Marjo-Riitta, additional, Arfan Ikram, M., additional, van den Ende, Joyce, additional, Uitterlinden, Andre G., additional, Hofman, Albert, additional, Amin, Najaf, additional, van Duijn, Cornelia, additional, Lehtimäki, Terho, additional, Ligthart, Lannie, additional, Hottenga, Jouke-Jan, additional, Vink, Jacqueline M., additional, Penninx, Brenda W., additional, Boomsma, Dorret I., additional, Schürks, Markus, additional, Jakobsson, Finnbogi, additional, Schoenen, Jean, additional, Heath, Andrew C., additional, Madden, Pamela A.F., additional, Göbel, Hartmut, additional, Heinze, Axel, additional, Heinze-Kuhn, Katja, additional, Schreiber, Stefan, additional, Daly, Mark J., additional, Alexander, Michael, additional, Raitakari, Olli, additional, and Strachan, David P., additional

Published
2015
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247. Systematic re-evaluation of genes from candidate gene association studies in migraine using a large genome-wide association data set

Author

de Vries, Boukje, primary, Anttila, Verneri, additional, Freilinger, Tobias, additional, Wessman, Maija, additional, Kaunisto, Mari A, additional, Kallela, Mikko, additional, Artto, Ville, additional, Vijfhuizen, Lisanne S, additional, Göbel, Hartmut, additional, Dichgans, Martin, additional, Kubisch, Christian, additional, Ferrari, Michel D, additional, Palotie, Aarno, additional, Terwindt, Gisela M, additional, and van den Maagdenberg, Arn MJM, additional

Published
2015
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248. BRF1 mutations alter RNA polymerase III–dependent transcription and cause neurodevelopmental anomalies

Author

Borck, Guntram, primary, Hög, Friederike, additional, Dentici, Maria Lisa, additional, Tan, Perciliz L., additional, Sowada, Nadine, additional, Medeira, Ana, additional, Gueneau, Lucie, additional, Thiele, Holger, additional, Kousi, Maria, additional, Lepri, Francesca, additional, Wenzeck, Larissa, additional, Blumenthal, Ian, additional, Radicioni, Antonio, additional, Schwarzenberg, Tito Livio, additional, Mandriani, Barbara, additional, Fischetto, Rita, additional, Morris-Rosendahl, Deborah J., additional, Altmüller, Janine, additional, Reymond, Alexandre, additional, Nürnberg, Peter, additional, Merla, Giuseppe, additional, Dallapiccola, Bruno, additional, Katsanis, Nicholas, additional, Cramer, Patrick, additional, and Kubisch, Christian, additional

Published
2015
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249. Can lesions to the motor cortex induce amyotrophic lateral sclerosis?

Author

Rosenbohm, Angela, Kassubek, Jan, Weydt, Patrick, Marroquin, Nicolai, Volk, Alexander E, Kubisch, Christian, Huppertz, Hans-Juergen, Weber, Markus, Andersen, Peter M, Weishaupt, Jochen H, Ludolph, Albert C, Rosenbohm, Angela, Kassubek, Jan, Weydt, Patrick, Marroquin, Nicolai, Volk, Alexander E, Kubisch, Christian, Huppertz, Hans-Juergen, Weber, Markus, Andersen, Peter M, Weishaupt, Jochen H, and Ludolph, Albert C

Abstract

A recent staging effort for amyotrophic lateral sclerosis (ALS) has demonstrated that the TDP-43 neuropathology may initiate focally in the motor cortex in the majority of patients. We searched our data bank for patients with lesions of the motor cortex which preceded disease onset. We performed a search of our patient- and MRI-data bank and screened 1,835 patients with amyotrophic lateral sclerosis for frontal lobe/motor cortex lesions. We found 18 patients with definite ALS who had documented and defined lesions of the motor cortex, which preceded the initial ALS symptoms by 8-42 years. In the vast majority (15/18) of the patients, the onset of ALS was closely related to the focal lesion since it started in a body region reflecting the damaged cortical area. The findings suggest that initial lesions to the motor cortex may be a contributing initiating factor in some patients with ALS or determine the site of onset in individuals pre-disposed to ALS.

Published
2014
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250. A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories

Author

Akimoto, Chizuru, Volk, Alexander E., van Blitterswijk, Marka, Van den Broeck, Marleen, Leblond, Claire S., Lumbroso, Serge, Camu, William, Neitzel, Birgit, Onodera, Osamu, van Rheenen, Wouter, Pinto, Susana, Weber, Markus, Smith, Bradley, Proven, Melanie, Talbot, Kevin, Keagle, Pamela, Chesi, Alessandra, Ratti, Antonia, van der Zee, Julie, Alstermark, Helena, Birve, Anna, Calini, Daniela, Nordin, Angelica, Tradowsky, Daniela C., Just, Walter, Daoud, Hussein, Angerbauer, Sabrina, DeJesus-Hernandez, Mariely, Konno, Takuya, Lloyd-Jani, Anjali, de Carvalho, Mamede, Mouzat, Kevin, Landers, John E., Veldink, Jan H., Silani, Vincenzo, Gitler, Aaron D., Shaw, Christopher E., Rouleau, Guy A., van den Berg, Leonard H., Van Broeckhoven, Christine, Rademakers, Rosa, Andersen, Peter M., Kubisch, Christian, Akimoto, Chizuru, Volk, Alexander E., van Blitterswijk, Marka, Van den Broeck, Marleen, Leblond, Claire S., Lumbroso, Serge, Camu, William, Neitzel, Birgit, Onodera, Osamu, van Rheenen, Wouter, Pinto, Susana, Weber, Markus, Smith, Bradley, Proven, Melanie, Talbot, Kevin, Keagle, Pamela, Chesi, Alessandra, Ratti, Antonia, van der Zee, Julie, Alstermark, Helena, Birve, Anna, Calini, Daniela, Nordin, Angelica, Tradowsky, Daniela C., Just, Walter, Daoud, Hussein, Angerbauer, Sabrina, DeJesus-Hernandez, Mariely, Konno, Takuya, Lloyd-Jani, Anjali, de Carvalho, Mamede, Mouzat, Kevin, Landers, John E., Veldink, Jan H., Silani, Vincenzo, Gitler, Aaron D., Shaw, Christopher E., Rouleau, Guy A., van den Berg, Leonard H., Van Broeckhoven, Christine, Rademakers, Rosa, Andersen, Peter M., and Kubisch, Christian

Abstract

Background The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories. Methods The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference. Results Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories. Conclusions Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.

Published
2014
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