MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome
Summary: 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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-05-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720306008 |
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| author | Ilaria Parenti Farah Diab Sara Ruiz Gil Eskeatnaf Mulugeta Valentina Casa Riccardo Berutti Rutger W.W. Brouwer Valerie Dupé Juliane Eckhold Elisabeth Graf Beatriz Puisac Feliciano Ramos Thomas Schwarzmayr Macarena Moronta Gines Thomas van Staveren Wilfred F.J. van IJcken Tim M. Strom Juan Pié Erwan Watrin Frank J. Kaiser Kerstin S. Wendt |
| author_facet | Ilaria Parenti Farah Diab Sara Ruiz Gil Eskeatnaf Mulugeta Valentina Casa Riccardo Berutti Rutger W.W. Brouwer Valerie Dupé Juliane Eckhold Elisabeth Graf Beatriz Puisac Feliciano Ramos Thomas Schwarzmayr Macarena Moronta Gines Thomas van Staveren Wilfred F.J. van IJcken Tim M. Strom Juan Pié Erwan Watrin Frank J. Kaiser Kerstin S. Wendt |
| author_sort | Ilaria Parenti |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-10T22:27:19Z |
| format | Article |
| id | doaj.art-919e3b69e9754004a2694650463d7df7 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T22:27:19Z |
| publishDate | 2020-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-919e3b69e9754004a2694650463d7df72022-12-22T01:31:09ZengElsevierCell Reports2211-12472020-05-01317MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange SyndromeIlaria Parenti0Farah Diab1Sara Ruiz Gil2Eskeatnaf Mulugeta3Valentina Casa4Riccardo Berutti5Rutger W.W. Brouwer6Valerie Dupé7Juliane Eckhold8Elisabeth Graf9Beatriz Puisac10Feliciano Ramos11Thomas Schwarzmayr12Macarena Moronta Gines13Thomas van Staveren14Wilfred F.J. van IJcken15Tim M. Strom16Juan Pié17Erwan Watrin18Frank J. Kaiser19Kerstin S. Wendt20Sektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany; Institute of Science and Technology (IST) Austria, Klosterneuburg, AustriaCentre National de la Recherche Scientifique, UMR6290, Rennes, France; Institut de Génétique et Développement de Rennes, Université de Rennes, Rennes, FranceSektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, GermanyDepartment of Cell Biology, Erasmus MC, Rotterdam, the NetherlandsDepartment of Cell Biology, Erasmus MC, Rotterdam, the NetherlandsInstitute of Human Genetics, Helmholtz Zentrum München, Neuherberg, GermanyErasmus MC, University Medical Center Rotterdam, Department of Cell Biology, Center for Biomics, the NetherlandsCentre National de la Recherche Scientifique, UMR6290, Rennes, France; Institut de Génétique et Développement de Rennes, Université de Rennes, Rennes, FranceSektion für Funktionelle Genetik am Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany; Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, GermanyInstitute of Human Genetics, Helmholtz Zentrum München, Neuherberg, GermanyUnit 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, SpainUnit 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, SpainInstitute of Human Genetics, Helmholtz Zentrum München, Neuherberg, GermanyDepartment of Cell Biology, Erasmus MC, Rotterdam, the NetherlandsDepartment of Cell Biology, Erasmus MC, Rotterdam, the NetherlandsErasmus MC, University Medical Center Rotterdam, Department of Cell Biology, Center for Biomics, the NetherlandsInstitute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, GermanyUnit 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, SpainCentre National de la Recherche Scientifique, UMR6290, Rennes, France; Institut de Génétique et Développement de Rennes, Université de Rennes, Rennes, FranceSektion 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; Corresponding authorDepartment of Cell Biology, Erasmus MC, Rotterdam, the Netherlands; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124720306008cohesinNIPBLMAU2Cornelia de Lange syndromecohesinopathytranscriptomopathy |
| spellingShingle | Ilaria Parenti Farah Diab Sara Ruiz Gil Eskeatnaf Mulugeta Valentina Casa Riccardo Berutti Rutger W.W. Brouwer Valerie Dupé Juliane Eckhold Elisabeth Graf Beatriz Puisac Feliciano Ramos Thomas Schwarzmayr Macarena Moronta Gines Thomas van Staveren Wilfred F.J. van IJcken Tim M. Strom Juan Pié Erwan Watrin Frank J. Kaiser Kerstin S. Wendt MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome Cell Reports cohesin NIPBL MAU2 Cornelia de Lange syndrome cohesinopathy transcriptomopathy |
| title | MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome |
| title_full | MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome |
| title_fullStr | MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome |
| title_full_unstemmed | MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome |
| title_short | MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome |
| title_sort | mau2 and nipbl variants impair the heterodimerization of the cohesin loader subunits and cause cornelia de lange syndrome |
| topic | cohesin NIPBL MAU2 Cornelia de Lange syndrome cohesinopathy transcriptomopathy |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720306008 |
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