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

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

doi:10.1038/s41467-026-71177-6

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

I Ilaria Parenti A Alina Hesters M Marta Gil-Salvador L Laura Duffy D Deniz Kanber J Jasmin Beygo J Jennifer Kerkhof L Laura Steenpaß E Elsa Leitão J Julia Woestefeld P Philip M. Boone E Emeline M. Kao L Lama AlAbdi H Hesham M. Aldhalaan F Fowzan S. Alkuraya M Muneera J. Alshammari S Stylianos E. Antonarakis D Donald Basel K Kevin Cassinari L Laurana de Polli Cellin A Amanda R. Clause A Alexander Augusto de Lima Jorge A Andréa de Castro Leal S Stephan C. Collins B Benjamin Durand J Juliane Eckhold M Mais O. Hashem P Parul Jayakar A Arif O. Khan K Kohji Kato R Regina Kubica G Gholson J. Lyon E Elaine Marchi J Julie McCarrier L Lara K. Kimmig S Seiji Mizuno G Gael Nicolas Y Yosuke Nishio T Tomoo Ogi J Juan Pié J Jordyn Prell B Beatriz Puisac F Feliciano J. Ramos E Emmanuelle Ranza C Claire Redin E Eric Rush S Shinji Saitoh H Hanan E. Shamseldin S Susan Starling E Esteban Astiazaran-Symonds S Sara H. Eltahir A Alma Kuechler B Bekim Sadikovic B Binnaz Yalcin K Kerstin S. Wendt F Frank J. Kaiser

Abstract

Abstract 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.

Download PDF View Original

APA MLA Chicago BibTeX RIS

Article Details

Journal Nature Communications

Volume / Issue Vol. 17, Issue 1

Published March 30, 2026

DOI 10.1038/s41467-026-71177-6

ISSN 2041-1723

Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio

ISSN: 2041-1723 Open Access Life Sciences

Authors (56)

I

Ilaria Parenti

A

Alina Hesters

M

Marta Gil-Salvador

L

Laura Duffy

D

Deniz Kanber

J

Jasmin Beygo

J

Jennifer Kerkhof

L

Laura Steenpaß

E

Elsa Leitão

J

Julia Woestefeld

P

Philip M. Boone

E

Emeline M. Kao

L

Lama AlAbdi

H

Hesham M. Aldhalaan

F

Fowzan S. Alkuraya

M

Muneera J. Alshammari

S

Stylianos E. Antonarakis

D

Donald Basel

K

Kevin Cassinari

L

Laurana de Polli Cellin

A

Amanda R. Clause

A

Alexander Augusto de Lima Jorge

A

Andréa de Castro Leal

S

Stephan C. Collins

B

Benjamin Durand

J

Juliane Eckhold

M

Mais O. Hashem

P

Parul Jayakar

A

Arif O. Khan

K

Kohji Kato

R

Regina Kubica

G

Gholson J. Lyon

E

Elaine Marchi

J

Julie McCarrier

L

Lara K. Kimmig

S

Seiji Mizuno

G

Gael Nicolas

Y

Yosuke Nishio

T

Tomoo Ogi

J

Juan Pié

J

Jordyn Prell

B

Beatriz Puisac

F

Feliciano J. Ramos

E

Emmanuelle Ranza

C

Claire Redin

E

Eric Rush

S

Shinji Saitoh

H

Hanan E. Shamseldin

S

Susan Starling

E

Esteban Astiazaran-Symonds

S

Sara H. Eltahir

A

Alma Kuechler

B

Bekim Sadikovic

B

Binnaz Yalcin

K

Kerstin S. Wendt

F

Frank J. Kaiser

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

Abstract

Article Details

Journal Info

Authors (56)

Related Articles from this Journal

Synthesis of adaptive 15N-nitrosyl-Co7 nanocluster for electrocatalytic C–H functionalization

Pan-Ebolavirus nanoparticle vaccine provides protection in rodents from lethal infection by Zaire and Sudan viruses

Multi-population GWAS meta-analysis identifies bladder cancer susceptibility loci and highlights genetic regulation of smoking-related risk

Genome-wide annotation of human multi-nucleotide variants reveals widespread functional differences from single nucleotide variants

Allele-specific chromatin architecture shapes imprinted domains and coordinates a distal enhancer and antisense transcription at the mouse Mest-Copg2 domain