Pathogenic variants in the cohesin loader subunit MAU2 underlie a distinct Cornelia de Lange Syndrome subtype

作者：Ilaria Parenti, Alina Hesters, Marta Gil-Salvador, Laura Duffy, Deniz Kanber, Jasmin Beygo, Jennifer Kerkhof, Laura Steenpaß, Elsa Leitão, Julia Woestefeld, Philip M. Boone, Emeline M. Kao, Lama Alabdi, Hesham Aldhalaan, Fowzan S. Alkuraya, Muneera Alshammari, Stylianos E. Antonarakis, Donald Basel, Kévin Cassinari, Laurana de Polli Cellin, Amanda Clause, Alexander Augusto de Lima Jorge, Andréa de Castro Leal, Stephan C. Collins, Benjamin Durand, Juliane Eckhold, Mais Hashem, Parul Jayakar, Arif O. Khan, Kohji Kato, Regina Kubica, Gholson J. Lyon, Elaine Marchi, Julie McCarrier, Lara Kristina Kimmig, Seiji Mizuno, Gael Nicolas, Yosuke Nishio, Tomoo Ogi, Juan Pié, Jordyn Prell, Beatriz Puisac, Feliciano J. Ramos, Emmanuelle Ranza, Claire Redin, Eric T. Rush, S. Saitoh, Hanan E. Shamseldin, Susan Starling, Esteban Astiazarán-Symonds, Sara H. Eltahir, Alma Kuechler, Bekim Sadikovic, Binnaz Yalcin, Kerstin S. Wendt, Frank J. Kaiser · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-71177-6 · 被引用次数：1 · 研究领域：Genomics and Chromatin Dynamics、Skin and Cellular Biology Research、Genomic variations and chromosomal abnormalities

The role of the cohesin complex depends on the cohesin loader proteins NIPBL and MAU2. While NIPBL variants are a major cause of Cornelia de Lange Syndrome (CdLS), the role of MAU2 in disease is unclear. We describe 18 individuals carrying 15 heterozygous MAU2 variants and demonstrate pathogenicity through functional analyses. In-frame MAU2 variants predominantly impair NIPBL-MAU2 interaction, whereas truncating variants cause MAU2 haploinsufficiency and lead to NIPBL reduction. Most individuals exhibit a DNA methylation profile compatible with the CdLS episignature. We also describe two MAU2-specific episignatures that reflect variant-dependent molecular consequences. Affected individuals display a wide range of phenotypes, from classic CdLS to milder presentations, with short stature and microcephaly as major features. A heterozygous Mau2 knockout mouse model recapitulates these traits, confirming the causal role of MAU2 disruption in vivo. Our study establishes MAU2 as a CdLS-associated gene and delineates a MAU2-related chromatinopathy with variable expressivity.