Variants Impair the Heterodimerization of the Cohesin Loader Subunitsand Cause Cornelia de Lange Syndrome
Authors Ilaria Parenti, Farah Diab, Sara Ruiz Gil, ...,Erwan Watrin, Frank J. Kaiser,Kerstin S. Wendt
IThe NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations in NIPBLaccount for most cases ofthe rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report aMAU2variant causingCdLS, 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 fornormal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fataloutcome of an out-of-frame single nucleotide duplication inNIPBL, engineered in two different cell lines,alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interactwith MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loadingcan occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protectiveagainst out-of-frame mutations that is potentially relevant for other genetic conditions.