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

Autor: van Doormaal PTC; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands., Ticozzi N; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center-Università degli Studi di Milano, Milan, Italy., Weishaupt JH; Department of Neurology, University of Ulm, Ulm, Germany., Kenna K; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts., Diekstra FP; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands., Verde F; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center-Università degli Studi di Milano, Milan, Italy., Andersen PM; Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden., Dekker AM; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands., Tiloca C; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy., Marroquin N; Institute of Human Genetics, University of Ulm, Ulm, Germany., Overste DJ; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands., Pensato V; Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy., Nürnberg P; Cologne Center for Genomics, University of Cologne, Cologne, Germany.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany., Pulit SL; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands., Schellevis RD; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands., Calini D; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy., Altmüller J; Cologne Center for Genomics, University of Cologne, Cologne, Germany.; Institute of Human Genetics, University of Cologne, Cologne, Germany., Francioli LC; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.; Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts., Muller B; Project MinE Foundation, Rotterdam, The Netherlands., Castellotti B; Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy., Motameny S; Cologne Center for Genomics, University of Cologne, Cologne, Germany., Ratti A; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center-Università degli Studi di Milano, Milan, Italy., Wolf J; Department of Neurology, Diakonissenkrankenhaus Mannheim, Mannheim, Germany., Gellera C; Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy., Ludolph AC; Department of Neurology, University of Ulm, Ulm, Germany., van den Berg LH; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands., Kubisch C; Institute of Human Genetics, Medical Centre Hamburg-Eppendorf, Hamburg, Germany., Landers JE; Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts., Veldink JH; Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands., Silani V; Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.; Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center-Università degli Studi di Milano, Milan, Italy., Volk AE; Institute of Human Genetics, Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2017 Nov; Vol. 38 (11), pp. 1534-1541. Date of Electronic Publication: 2017 Aug 03.
DOI: 10.1002/humu.23295
Abstrakt: The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 × 10 -15 ). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.
(© 2017 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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