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

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

doi:10.1016/j.celrep.2020.107647

Journal articles

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

I. Parenti ^{1, 2} F. Diab ³ S.R. Gil ¹ E. Mulugeta ⁴ V. Casa ⁴ R. Berutti ⁵ R.W.W. Brouwer ⁴ V. Dupe ³ J. Eckhold ¹ E. Graf ⁵ B. Puisac ⁶ F. Ramos ⁶ T. Schwarzmayr ⁵ M.M. Gines ⁴ T. van Staveren ⁴ W.F.J. van Ijcken ⁴ T.M. Strom ⁵ J. Pie ⁶ E. Watrin ³ F.J. Kaiser ^{1, 7, *} K.S. Wendt ^{4, *}

* Corresponding author

1 Universität zu Lübeck [Lübeck]

2 IST Austria - Institute of Science and Technology [Austria]

3 IGDR - Institut de Génétique et Développement de Rennes

4 Erasmus MC - Erasmus University Medical Center [Rotterdam]

5 HZM - Helmholtz-Zentrum München

6 University of Zaragoza - Universidad de Zaragoza [Zaragoza]

7 Universität Duisburg-Essen [Essen]

Abstract : 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. © 2020 The AuthorsParenti et al. describe mutations causative for CdLS that affect the interaction between NIPBL and MAU2, the two subunits of the cohesin loader complex. This study further reveals a protective mechanism that rescues NIPBL expression in the presence of early truncating variants by using alternative translation initiation site. © 2020 The Authors

Keywords : ChIP sequencing cohesin cohesinopathy Cornelia de Lange syndrome CRISPR-Cas9 MAU2 NIPBL rescue mechanism transcriptomopathy

Document type :

Journal articles

Domain :

Life Sciences [q-bio]

Complete list of metadata

Cited literature [68 references] Display Hide Download

https://hal-univ-rennes1.archives-ouvertes.fr/hal-02862830
Contributor : Laurent Jonchère <>
Submitted on : Friday, July 17, 2020 - 10:17:04 AM
Last modification on : Tuesday, January 19, 2021 - 4:50:10 PM
Long-term archiving on: : Monday, November 30, 2020 - 11:52:33 PM

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

File

Licence

Identifiers

Collections

Citation

Export

Metrics

26

70

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

File

Licence

Identifiers

Collections

Citation

Export

Share

Metrics

26

70