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; Erwan 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 Erwan 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

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Journal articles

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Life Sciences [q-bio]

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

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

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