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2 results on '"Müller, Thoma"'

1. Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

Author

James R. A. Skipworth, Sebastian Krug, Florence Bühler, Sebastian Gimpfl, Joachim Mössner, Anke Tönjes, Atsushi Masamune, Adrian Saftoiu, Roland H. Pfützer, Marcella Rietschel, Heiko Witt, Felix Stickel, Jens Werner, Peter Kovacs, Nicole Soranzo, Constantin Zimmer, Martin Ziegler, Helmut Laumen, Holger Kirsten, Marco J. Bruno, Joost P.H. Drenth, Markus M. Lerch, Markus M. Nöthen, Claus Hellerbrand, Annette Peters, Philippe Lévy, Jian-Min Chen, Monika Ridinger, Giulia Martina Cavestro, Emmanuelle Masson, Milena Di Leo, Peter Simon, Peter Bugert, Péter Hegyi, Karl Mann, Miklós Sahin-Tóth, Pier Alberto Testoni, Núria Malats, Rene H. M. te Morsche, Konstantin Strauch, Stephen P. Pereira, Josef Frank, Norbert Wodarz, Halina Cichoż-Lach, Jonas Rosendahl, Alexander Schneider, Marcus Hollenbach, Olfert Landt, Markus Löffler, Sergio Pedrazzoli, Volker Keim, Matthias Löhr, Marie Motyka, Sebastian Mueller, Ralph Burkhardt, Antoni Farré, Heidi Griesmann, Falk Kiefer, Giovanni Malerba, Claudia Ruffert, Markus Scholz, Francisco X. Real, Maren Ludwig, Eszter Hegyi, Harald Grallert, Hana Algül, Vinciane Rebours, Eva Rösmann, Frank Ulrich Weiss, Sonja Mohr, Robert Grützmann, Sevastitia Iordache, Michael Soyka, Milan Macek, Peter Lichtner, Patrick Michl, Claude Férec, Giovanni Gambaro, Michael Stumvoll, Katharina Seltsam, Thomas Müller, Grazyna Jurkowska, Ewa Małecka-Panas, Sebastian Beer, Julia Mayerle, Hans-Ulrich Schulz, Lena Werner, Publica, Rosendahl, Jona, Kirsten, Holger, Hegyi, Eszter, Kovacs, Peter, Weiss, Frank Ulrich, Laumen, Helmut, Lichtner, Peter, Ruffert, Claudia, Chen, Jian min, Masson, Emmanuelle, Beer, Sebastian, Zimmer, Constantin, Seltsam, Katharina, Algül, Hana, Bühler, Florence, Bruno, Marco J, Bugert, Peter, Burkhardt, Ralph, Cavestro, GIULIA MARTINA, Cichoz lach, Halina, Farré, Antoni, Frank, Josef, Gambaro, Giovanni, Gimpfl, Sebastian, Grallert, Harald, Griesmann, Heidi, Grützmann, Robert, Hellerbrand, Clau, Hegyi, Péter, Hollenbach, Marcu, Iordache, Sevastitia, Jurkowska, Grazyna, Keim, Volker, Kiefer, Falk, Krug, Sebastian, Landt, Olfert, Leo, Milena Di, Lerch, Markus M, Lévy, Philippe, Löffler, Marku, Löhr, Matthia, Ludwig, Maren, Macek, Milan, Malats, Nuria, Malecka panas, Ewa, Malerba, Giovanni, Mann, Karl, Mayerle, Julia, Mohr, Sonja, Te Morsche, Rene H. M, Motyka, Marie, Mueller, Sebastian, Müller, Thoma, Nöthen, Markus M, Pedrazzoli, Sergio, Pereira, Stephen P, Peters, Annette, Pfützer, Roland, Real, Francisco X, Rebours, Vinciane, Ridinger, Monika, Rietschel, Marcella, Rösmann, Eva, Saftoiu, Adrian, Schneider, Alexander, Schulz, Hans ulrich, Soranzo, Nicole, Soyka, Michael, Simon, Peter, Skipworth, Jame, Stickel, Felix, Strauch, Konstantin, Stumvoll, Michael, Testoni, PIER ALBERTO, Tönjes, Anke, Werner, Lena, Werner, Jen, Wodarz, Norbert, Ziegler, Martin, Masamune, Atsushi, Mössner, Joachim, Férec, Claude, Michl, Patrick, Joost, P. H. Drenth, Witt, Heiko, Scholz, Marku, Sahin tóth, Miklós, and Gastroenterology & Hepatology

Subjects
0301 basic medicine, Linkage disequilibrium, medicine.medical_specialty, Settore MED/12 - GASTROENTEROLOGIA, Population, Genome Wide Association Study, Chronic Pancreatitis, Genetic Rearrangement, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Gastroenterology, chronic pancreatitis, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Genetic predisposition, medicine, Allele, education, Genetics, education.field_of_study, medicine.disease, ddc, genetic rearrangement, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Genome wide association study, Pancreatitis, chronic pancreatiti, Chronic pancreatitis, Genetic rearrangement
Abstract

ObjectiveAlcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus.Design1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used.ResultsWe replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk.ConclusionAn inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.

Published
2018

2. POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking

Author

Hui Jiang, Francesca Romana Di Raimo, Subreena Simrick, Giorgio Tasca, Jianguo Zhang, Fabiana Fattori, C. Scotton, Claudio Rapezzi, Thomas Brand, Bruno Dallapiccola, Rita Selvatici, Niels Decher, Alexander Froese, Viacheslav O. Nikolaev, Antonello Pietrangelo, Roland F.R. Schindler, Jun Wang, Fabrizio Drago, Enrico Bertini, Susanne Rinné, Marcella Neri, Alessandra Ferlini, Thorsten Schwerte, Kar Lai Poon, Thomas Müller, Christiane Grunert, Wenyan Li, Eloisa Arbustini, Mingyan Fang, Xun Xu, Chiara Passarelli, Beatriz Ortiz-Bonnin, Padmini Sarathchandra, Francesca Gualandi, Schindler, Roland F. R., Scotton, Chiara, Zhang, Jianguo, Passarelli, Chiara, Ortiz-Bonnin, Beatriz, Simrick, Subreena, Schwerte, Thorsten, Poon, Kar-Lai, Fang, Mingyan, Rinné, Susanne, Froese, Alexander, Nikolaev, Viacheslav O., Grunert, Christiane, Müller, Thoma, Tasca, Giorgio, Sarathchandra, Padmini, Drago, Fabrizio, Dallapiccola, Bruno, Rapezzi, Claudio, Arbustini, Eloisa, Romana Di Raimo, Francesca, Neri, Marcella, Selvatici, Rita, Gualandi, Francesca, Fattori, Fabiana, Pietrangelo, Antonello, Li, Wenyan, Jiang, Hui, Xu, Xun, Bertini, Enrico, Decher, Niel, Wang, Jun, Brand, Thoma, Ferlini, Alessandra, Medical Research Council (MRC), British Heart Foundation, and The Magdi Yacoub Institute

Subjects
0301 basic medicine, Male, Pathology, Muscle Proteins, Research & Experimental Medicine, DOMAIN-CONTAINING PROTEINS, domain containing proteins, Membrane Potentials, Cyclic AMP, Missense mutation, Muscular dystrophy, Child, Zebrafish, Membrane Protein, Cardiac muscle cell, Aged, 80 and over, biology, Medicine (all), Aged, Animals, Arrhythmias, Cardiac, Humans, Membrane Proteins, Middle Aged, Muscular Dystrophies, Limb-Girdle, Mutation, Potassium Channels, Tandem Pore Domain, Protein Transport, STRESS-MEDIATED MODULATION, General Medicine, 11 Medical And Health Sciences, medicine.anatomical_structure, Medicine, Research & Experimental, SKELETAL-MUSCLE, HEART, POTASSIUM CHANNEL, muscular dystrophy, arrhythmia, ITGA7, Life Sciences & Biomedicine, Human, Research Article, medicine.medical_specialty, HL-1 CELLS, Immunology, cardiac pacemakin, Membrane Potential, NO, HL1 cell, 03 medical and health sciences, Internal medicine, medicine, KINASE, Allele, skeletal muscle, Science & Technology, COMPLEX, Animal, Cardiac arrhythmia, Skeletal muscle, stress mediated modulation, domain containing proteins, skeletal muscle, cardiac pacemakin, potassium channel, HL1 cell, zebrafish, heart, kinase, biology.organism_classification, medicine.disease, 030104 developmental biology, Endocrinology, stress mediated modulation, CARDIAC PACEMAKING, Cell Adhesion Molecules
Abstract

The Popeye domain-containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1(S201F) displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1(S201F) and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1(S201F) in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1(S191F)) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases. peerReviewed

Published
2014

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