STAG2-truncating variants reveal a mosaic STAG2 inactivation pattern and compensatory mechanisms involving cohesin complex remodeling

TL;DR

Females with STAG2 mutations show a mix of STAG2 expression and use alternative proteins to compensate, explaining varied symptoms.

Contribution

Discovery of a chimeric cohesin complex and compensatory mechanisms in STAG2-deficient cells.

Findings

Skewed X chromosome inactivation favors the mutant STAG2 allele in most cases.

STAG2-negative cells show a proliferative advantage without cohesion or DNA repair defects.

STAG3 is upregulated and forms a new cohesin complex in somatic cells.

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.

•Females with germline STAG2-truncating variants show skewed X chromosome inactivation•STAG2-negative cells seem to have a proliferative advantage over STAG2-positive cells•STAG3 is expressed in 2 of 4 skin fibroblast samples and might substitute for STAG2

Females with germline STAG2-truncating variants show skewed X chromosome inactivation

STAG2-negative cells seem to have a proliferative advantage over STAG2-positive cells

STAG3 is expressed in 2 of 4 skin fibroblast samples and might substitute for STAG2

Health sciences; Medicine; Clinical genetics; Biological sciences; Biochemistry; Physiology

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