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Parenti, I.* ; Diab, F.* ; Gil, S.R.* ; Mulugeta, E.* ; Casa, V.* ; Berutti, R. ; Brouwer, R.W.W.* ; Dupé, V.* ; Eckhold, J.* ; Graf, E. ; Puisac, B.* ; Ramos, F.* ; Schwarzmayr, T. ; Gines, M.M.* ; van Staveren, T.* ; van IJcken, W.F.J.* ; Strom, T.M. ; Pié, J.* ; Watrin, E.* ; Kaiser, F.J.* ; Wendt, K.S.*

MAU2 and NIPBL variants impair the heterodimerization of the cohesin loader subunits and cause Cornelia de Lange syndrome.

Cell Rep. 31:107647 (2020)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Chip Sequencing ; Cohesin ; Cohesinopathy ; Cornelia De Lange Syndrome ; Crispr-cas9 ; Mau2 ; Nipbl ; Rescue Mechanism ; Transcriptomopathy; Sister-chromatid Cohesion; Mutations Cause; Gene-expression; Read Alignment; Binding; Spectrum; Scc2; Individuals; Complex
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 31, Issue: 7, Pages: , Article Number: 107647 Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Institute of Human Genetics (IHG)