STAG2-truncating variants reveal a mosaic STAG2 inactivation pattern and compensatory mechanisms involving cohesin complex remodeling
Abstract
Cohesin plays a central role in three-dimensional genome organization and transcriptional regulation, with functional diversity determined by incorporation of distinct STAG subunits. Pathogenic variants in the X-linked STAG2 gene cause a rare cohesinopathy with variable clinical manifestations. Molecular analyses of fibroblasts from females carrying germline STAG2-truncating variants revealed highly skewed X chromosome inactivation favoring the mutant allele, resulting in loss of STAG2 expression in most cases. STAG2-deficient cells displayed a proliferative advantage and transcriptional alterations without detectable defects in sister chromatid cohesion or DNA repair. Notably, compensatory upregulation of STAG1 and ectopic expression of the germ cell-specific paralog STAG3 were observed, leading to the formation of a previously unrecognized chimeric cohesin complex in somatic cells. These findings suggest that females with STAG2-truncating variants exhibit mosaicism for STAG2 expression and compensatory STAG3 incorporation, providing mechanistic insight into the phenotypic variability observed in STAG2-associated cohesinopathies.
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BibTeX
@article{gines2026stag2truncating,
title = {{STAG2-truncating variants reveal a mosaic STAG2 inactivation pattern and compensatory mechanisms involving cohesin complex remodeling}},
author = {Macarena Moronta Gines and Marja W. Wessels and Valentina Casa and Thomas van Staveren and Amber Hof and Wendy K. Chung and Marjolaine Willems and Anna Sandestig and Irina Huening and Peter Turnpenny and Mathilde Lefebvre and Ilaria Parenti and Frank J. Kaiser and Jeroen Demmers and Wilfred F.J. van Ijcken and Kerstin S. Wendt},
journal = {iScience},
year = {2026},
month = sep,
doi = {10.1016/j.isci.2025.114195},
url = {https://hal.science/hal-05738655v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - STAG2-truncating variants reveal a mosaic STAG2 inactivation pattern and compensatory mechanisms involving cohesin complex remodeling
AU - Macarena Moronta Gines
AU - Marja W. Wessels
AU - Valentina Casa
AU - Thomas van Staveren
AU - Amber Hof
AU - Wendy K. Chung
AU - Marjolaine Willems
AU - Anna Sandestig
AU - Irina Huening
AU - Peter Turnpenny
AU - Mathilde Lefebvre
AU - Ilaria Parenti
AU - Frank J. Kaiser
AU - Jeroen Demmers
AU - Wilfred F.J. van Ijcken
AU - Kerstin S. Wendt
PY - 2026
DA - 2026/09/04
JO - iScience
DO - 10.1016/j.isci.2025.114195
UR - https://hal.science/hal-05738655v1
AB - Cohesin plays a central role in three-dimensional genome organization and transcriptional regulation, with functional diversity determined by incorporation of distinct STAG subunits. Pathogenic variants in the X-linked STAG2 gene cause a rare cohesinopathy with variable clinical manifestations. Molecular analyses of fibroblasts from females carrying germline STAG2-truncating variants revealed highly skewed X chromosome inactivation favoring the mutant allele, resulting in loss of STAG2 expression in most cases. STAG2-deficient cells displayed a proliferative advantage and transcriptional alterations without detectable defects in sister chromatid cohesion or DNA repair. Notably, compensatory upregulation of STAG1 and ectopic expression of the germ cell-specific paralog STAG3 were observed, leading to the formation of a previously unrecognized chimeric cohesin complex in somatic cells. These findings suggest that females with STAG2-truncating variants exhibit mosaicism for STAG2 expression and compensatory STAG3 incorporation, providing mechanistic insight into the phenotypic variability observed in STAG2-associated cohesinopathies.
SN - 2589-0042
ER -