MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome.

Autor:	Parenti I; Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany; Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria., Diab F; Centre National de la Recherche Scientifique, UMR6290, Rennes, France; Institut de Génétique et Développement de Rennes, Université de Rennes, Rennes, France., Gil SR; Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany., Mulugeta E; Department of Cell Biology, Erasmus MC, Rotterdam, the Netherlands., Casa V; Department of Cell Biology, Erasmus MC, Rotterdam, the Netherlands., Berutti R; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Brouwer RWW; Erasmus MC, University Medical Center Rotterdam, Department of Cell Biology, Center for Biomics, the Netherlands., Dupé V; Centre National de la Recherche Scientifique, UMR6290, Rennes, France; Institut de Génétique et Développement de Rennes, Université de Rennes, Rennes, France., Eckhold J; Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany; Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany., Graf E; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Puisac B; Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, 50009 Zaragoza, Spain., Ramos F; Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, 50009 Zaragoza, Spain., Schwarzmayr T; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany., Gines MM; Department of Cell Biology, Erasmus MC, Rotterdam, the Netherlands., van Staveren T; Department of Cell Biology, Erasmus MC, Rotterdam, the Netherlands., van IJcken WFJ; Erasmus MC, University Medical Center Rotterdam, Department of Cell Biology, Center for Biomics, the Netherlands., Strom TM; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany., Pié J; Unit of Clinical Genetics and Functional Genomics, Department of Pharmacology-Physiology and Paediatrics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and ISS-Aragon, 50009 Zaragoza, Spain., Watrin E; Centre National de la Recherche Scientifique, UMR6290, Rennes, France; Institut de Génétique et Développement de Rennes, Université de Rennes, Rennes, France., Kaiser FJ; Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany; Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany; DZHK e.V. (German Center for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Lübeck, Germany. Electronic address: frank.kaiser@uk-essen.de., Wendt KS; Department of Cell Biology, Erasmus MC, Rotterdam, the Netherlands. Electronic address: k.wendt@erasmusmc.nl.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2020 May 19; Vol. 31 (7), pp. 107647.
DOI:	10.1016/j.celrep.2020.107647
Abstrakt:	The NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations in NIPBL account for most cases of the rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report a MAU2 variant causing CdLS, a deletion of seven amino acids that impairs the interaction between MAU2 and the NIPBL N terminus. Investigating this interaction, we discovered that MAU2 and the NIPBL N terminus are largely dispensable for normal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fatal outcome of an out-of-frame single nucleotide duplication in NIPBL, engineered in two different cell lines, alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interact with MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loading can occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protective against out-of-frame mutations that is potentially relevant for other genetic conditions. Competing Interests: Declaration of Interests The authors declare no competing interests. (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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