MAU2 and NIPBL variants in Cornelia de Lange syndrome reveal MAU2-independent loading of cohesin and uncover protective mechanisms against early truncating mutations in NIPBL

For its association with chromatin, the cohesin complex depends on a heterodimer formed by NIPBL and MAU2. Variants in NIPBL are the main cause of CdLS and result in NIPBL haploinsufficiency. Using CRISPR, we generated cells homozygous for an out-of-frame duplication in NIPBL. Remarkably, alternative translation initiation rescued NIPBL expression in these cells and produced an N-terminally truncated NIPBL that lacks MAU2-interaction domain, causing a dramatic reduction of MAU2 protein levels while a lot of NIPBL functions remain intact. ChIP sequencing of SMC3, NIPBL wild type (WT) vs CRISPR edited cell HEK293T lines using HiSeq2500 sequencer. In total 9 samples are analysed. Smc3: WT vs CRISPR edited, 4 samples in total including input. NIPBL: WT vs CRISPR edited, 5 samples in total, including input.