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<p>The role of the cohesin complex depends on the cohesin loader proteins NIPBL and MAU2. While <i>NIPBL</i> variants are a major cause of Cornelia de Lange Syndrome (CdLS), the role of <i>MAU2</i> in disease is unclear. We describe 18 individuals carrying 15 heterozygous <i>MAU2</i> variants and demonstrate pathogenicity through functional analyses. In-frame <i>MAU2</i> variants predominantly impair NIPBL–MAU2 interaction, whereas truncating variants cause <i>MAU2</i> haploinsufficiency and lead to NIPBL reduction. Most individuals exhibit a DNA methylation profile compatible with the CdLS episignature. We also describe two <i>MAU2</i>-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 <i>Mau2</i> knockout mouse model recapitulates these traits, confirming the causal role of <i>MAU2</i> disruption in vivo. Our study establishes <i>MAU2</i> as a CdLS-associated gene and delineates a <i>MAU2</i>-related chromatinopathy with variable expressivity.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月30日

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  • 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 M. Aldhalaan,
  • Fowzan S. Alkuraya,
  • Muneera J. Alshammari,
  • Stylianos E. Antonarakis,
  • Donald Basel,
  • Kevin Cassinari,
  • Laurana de Polli Cellin,
  • Amanda R. Clause,
  • Alexander Augusto de Lima Jorge,
  • Andréa de Castro Leal,
  • Stephan C. Collins,
  • Benjamin Durand,
  • Juliane Eckhold,
  • Mais O. Hashem,
  • Parul Jayakar,
  • Arif O. Khan,
  • Kohji Kato,
  • Regina Kubica,
  • Gholson J. Lyon,
  • Elaine Marchi,
  • Julie McCarrier,
  • Lara K. Kimmig,
  • Seiji Mizuno,
  • Gael Nicolas,
  • Yosuke Nishio,
  • Tomoo Ogi,
  • Juan Pié,
  • Jordyn Prell,
  • Beatriz Puisac,
  • Feliciano J. Ramos,
  • Emmanuelle Ranza,
  • Claire Redin,
  • Eric Rush,
  • Shinji Saitoh,
  • Hanan E. Shamseldin,
  • Susan Starling,
  • Esteban Astiazaran-Symonds,
  • Sara H. Eltahir,
  • Alma Kuechler,
  • Bekim Sadikovic,
  • Binnaz Yalcin,
  • Kerstin S. Wendt,
  • Frank J. Kaiser

摘要

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.