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.Parenti 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.

ChIP sequencing, cohesin, cohesinopathy, Cornelia de Lange syndrome, CRISPR-Cas9, MAU2, NIPBL, rescue mechanism, transcriptomopathy,
Cell Reports
Biophysical Genomics, Department Cell Biology & Genetics

Parenti, I, Diab, F. (Farah), Gil, S.R. (Sara Ruiz), Mulugeta, E. (Eskeatnaf), Casa, V. (Valentina), Berutti, R. (Riccardo), … Wendt, K.S. (2020). MAU2 and NIPBL Variants Impair the Heterodimerization of the Cohesin Loader Subunits and Cause Cornelia de Lange Syndrome. Cell Reports, 31(7). doi:10.1016/j.celrep.2020.107647