Alternative titles; symbols
HGNC Approved Gene Symbol: STAG2
Cytogenetic location: Xq25 Genomic coordinates (GRCh38): X:123,960,560-124,102,656 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq25 | Holoprosencephaly 13, X-linked | 301043 | X-linked dominant; X-linked recessive | 3 |
| Mullegama-Klein-Martinez syndrome | 301022 | X-linked | 3 |
The STAG2 gene encodes one of the core proteins of the cohesin complex, a conserved functional unit involved in DNA replication, gene expression, heterochromatin formation, DNA repair, and sister chromatid cohesion. The cohesin complex consists of 4 core proteins: SMC1A (300040), SMC3 (606062), RAD21 (606462), and STAG1 (604358)/STAG2 (summary by Mullegama et al., 2017).
Stromal cells from blood-forming organs provide the physical support for hematopoietic cell organization. The stroma also produces signals for seeding, renewal, proliferation, and differentiation of stem cells. By screening a human thymus cDNA library with a mouse SA1 cDNA, Carramolino et al. (1997) isolated a cDNA encoding STAG2, which they named SA2. The deduced protein has 1,162 amino acids, and its sequence is 78% similar to that of STAG1 (604358).
In mouse embryos, Kruszka et al. (2019) found expression of the Stag2 gene in anterior neural folds, the neuroectoderm, and adjacent mesenchyme of the developing brain. The findings suggested a role in forebrain patterning.
By immunoprecipitation and immunoblot analyses, Sumara et al. (2000) showed that STAG2 is expressed as an approximately 140-kD protein that assembles with the cohesin proteins SMC1 (SMC1A), SMC3, and SCC1 (RAD21). The cohesin complex also coprecipitates with PDS5 (see 613200), but in a less stable way than the proteins in the cohesin assembly. Immunofluorescence microscopy demonstrated nonnucleolar expression of STAG2 in interphase and early prophase, but expression did not occur again until telophase, with the onset of chromosome decondensation. The expression pattern paralleled those of STAG1, PDS5, and the other cohesin subunits. Cohesin dissociation was found to be independent of the anaphase-promoting complex (APC; see 603462). Sumara et al. (2000) proposed that there is a prophase pathway that removes the bulk of cohesin complexes, thereby enabling chromosome condensation while releasing cohesion between chromosome arms, and that residual cohesin is removed by an anaphase pathway.
Crystal Structure
Li et al. (2020) showed that a segment within the CCCTC-binding factor (CTCF; 604167) N terminus interacts with the SA2-SCC1 (600925) subunits of human cohesin. They reported a crystal structure of SA2-SCC1 in complex with CTCF at a resolution of 2.7 angstroms, which revealed the molecular basis of the interaction. Li et al. (2020) demonstrated that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF binding sites. A similar motif is present in a number of established and newly identified cohesin ligands, including the cohesin release factor WAPL (610754). Li et al. (2020) concluded that their data suggested that CTCF enables the formation of chromatin loops by protecting cohesin against loop release.
Renault et al. (2011) presented evidence suggesting that the STAG2 gene may play a role in familial skewed X inactivation-2 (SXI2; 300179). In a Canadian family with hemophilia A (HEMA; 306700) in which 3 affected females showed skewed X inactivation (Renault et al., 2007), Renault et al. (2011) found linkage to a 16.7-cM region on Xq25-q27, which contains the STAG2 gene. Although no pathogenic mutations were found in STAG2, its function as a core component of the ring-like cohesin complex involved in sister chromatid cohesion during mitosis made it a candidate gene for the trait.
Ding et al. (2018) found that depletion of STAG2 produced excessive interferon (IFN) expression and resulted in resistance to rotavirus replication in human cultured cell lines and human intestinal enteroids. STAG2 deficiency induced host genomic DNA damage and led to increased levels of cytoplasmic DNA, which activated the CGAS (613973)-STING (TMEM173; 612374) DNA-sensing pathway to express IFN and IFN-stimulated genes. These processes enabled host cells to enter an antiviral state, rendering them resistant to rotavirus infection.
Using biochemical reconstitution, Davidson et al. (2019) found that single human cohesin complexes form DNA loops symmetrically at rates up to 2.1 kilobase pairs per second. Loop formation and maintenance depend on cohesin's ATPase activity and on NIPBL (608667)-MAU2 (614560), but not on topologic entrapment of DNA by cohesin (components include SMC3, SMC1A, STAG1, and STAG2). During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, which indicates that they generate loops by extrusion. Davidson et al. (2019) concluded that their results showed that cohesin and NIPBL-MAU2 form an active holoenzyme that interacts with DNA either pseudotopologically or nontopologically to extrude genomic interphase DNA into loops.
Mullegama-Klein-Martinez Syndrome
In an 8-year-old girl (patient 1) with Mullegama-Klein-Martinez syndrome (MKMS; 301022), Mullegama et al. (2017) identified a de novo heterozygous nonsense mutation in the STAG2 gene (R69X; 300826.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to encode a protein lacking 3 essential protein domains. Western blot analysis of patient cells showed decreased amounts of STAG2 protein compared to controls, and the authors noted that the mutation may trigger nonsense-mediated mRNA decay. Analysis of metaphase in patient cells showed a reduction in premature sister chromatid separation compared to controls, although karyotypes were normal and there were no significant aneuploidies. Mullegama et al. (2017) postulated a loss-of-function mechanism causing haploinsufficiency, and noted that some of the other functions of STAG2, such as the regulation of gene expression, may also be disrupted by the mutation. Subsequent searching of the DECIPHER database identified 2 additional girls with overlapping clinical features who had de novo heterozygous variants in the STAG2 gene (R604Q and c.1913_1922del). None of the variants were present in the 1000 Genomes Project or ExAC databases, but functional studies of the latter 2 mutations were not performed.
In 5 affected males from a large Brazilian family with MKMS, Soardi et al. (2017) identified a hemizygous missense mutation in the STAG2 gene (S327N; 300826.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. There were at least 2 confirmed healthy female carriers of the mutation. Analysis of patient fibroblasts showed that the mutant protein was expressed in normal amounts and localized properly to the nucleus, and there were no defects in sister chromatid cohesion. However, patient cells showed cell cycle abnormalities, including increased percentage of G2/M cells and upregulation of genes involved in cell division, mitotic regulation, and DNA replication compared to controls. These findings were consistent with a defect in transcriptional regulation. Expression of the mutation in HeLa cells showed decreased binding of the mutant protein to SCC1 and other cohesin regulators.
In a 4-year-old boy with MKMS, Mullegama et al. (2019) identified a de novo hemizygous missense mutation in the STAG2 gene (K1009N; 300826.0003). The mutation was found by exome sequencing; functional studies of the variant and studies of patient cells were not performed. Mullegama et al. (2019) postulated that females, who carry 2 copies of the STAG2 gene, are able to survive with deleterious de novo variants, but show severe phenotypes. In contrast, males, who have only 1 copy of the gene, are unable to survive with similar variants due to early embryonic lethality. Males can survive with less damaging variants, such as missense mutations, and usually present with a milder phenotype.
Yuan et al. (2019) reported 5 unrelated patients, including 4 females and 1 male, with MKMS who had de novo heterozygous or hemizygous mutations in the STAG2 gene (see, e.g., 300826.0004-300826.0006). Three of the 4 females had truncating mutations, whereas the male had a missense mutation; none of the mutations were found in the ExAC or Exome Sequencing Project databases. Yuan et al. (2019) postulated loss of function as the presumed mechanism, although functional studies of the variants and studies of patient cells were not performed. The patients were ascertained from a large cohort of over 10,000 patients referred for exome sequencing.
X-Linked Holoprosencephaly 13
In 6 unrelated girls with X-linked HPE13, Kruszka et al. (2019) identified heterozygous nonsense, frameshift, or splice site mutations in the STAG2 gene (see, e.g., 300826.0001; 300826.0009-300826.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. Four mutations occurred de novo, 1 was presumed to occur de novo, and 1 was inherited from a presumably unaffected mother, suggesting either skewed X inactivation (not tested) or incomplete penetrance. Functional studies of the variants and studies of patient cells were not performed, but all of the variants were predicted to result in a loss of function (LOF) and haploinsufficiency. The findings of only affected females suggested that LOF variants in this gene are lethal in males. Kruszka et al. (2019) noted that STAG2 undergoes complete X inactivation. Knockdown of the STAG2 gene in human neural progenitor cells resulted in upregulation of ZIC2 (603073) and FGFR1 (136350). Although the significance of these findings was unclear, they demonstrated that loss of STAG2 perturbs the expression of genes involved in HPE.
Role in Xq25 Duplication Syndrome
For discussion of a possible association between duplication of the STAG2 gene and X-linked impaired intellectual development, see 300979.
Role in Cancer
Solomon et al. (2011) found that diverse range of tumor types harbor deletions or inactivating mutations of STAG2, the gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, Solomon et al. (2011) found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in 2 aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, Solomon et al. (2011) concluded that genetic disruption of cohesin is a cause of aneuploidy in human cancer.
Solomon et al. (2013) reported the discovery of truncating mutations in STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary noninvasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Solomon et al. (2013) stated that their studies suggested that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells.
Guo et al. (2013) reported genomic analysis of transitional cell carcinoma (TCC) by both whole-genome and whole-exome sequencing in 99 individuals. Beyond confirming recurrent mutations in genes previously identified as being mutated in TCC, Guo et al. (2013) identified additional altered genes and pathways that were implicated in TCC. Guo et al. (2013) discovered frequent alterations in STAG2 (300826) and ESPL1 (604143), both involved in the sister chromatid cohesion and segregation process. Overall, 32 of the 99 tumors (32%) harbored genetic alterations in the sister chromatid cohesion and segregation process.
Balbas-Martinez et al. (2013) found that STAG2 was significantly and commonly mutated or lost in urothelial bladder cancer, mainly in tumors of low stage or grade, and that its loss was associated with improved outcome. Loss of expression was often observed in chromosomally stable tumors, and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in nonexpressing cells led to reduced colony formation. Balbas-Martinez et al. (2013) found that STAG2 is a novel urothelial bladder cancer tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy.
An article by Aoi et al. (2019) described 2 patients with nonsense mutations in the STAG2 gene: a male fetus (patient 1) with HPE13 who had a hemizygous nonsense mutation (R1033X) and a female with MKMS who had a nonsense mutation (W743X). Patient 1 was in fact a female. Because the key conclusions of the article depended on the sex of the patients, the article was retracted.
Mullegama-Klein-Martinez Syndrome
In an 8-year-old girl (patient 1) with Mullegama-Klein-Martinez syndrome (MKMS; 301022), Mullegama et al. (2017) identified a de novo heterozygous c.205C-T transition (c.205C-T, NM_001042749.1) in exon 5 of the STAG2 gene, resulting in an arg69-to-ter (R69X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was predicted to encode a protein lacking 3 essential protein domains. The variant was not found in the 1000 Genomes Project or ExAC databases. Western blot analysis of patient cells showed decreased amounts of STAG2 protein compared to controls, and the authors noted that the mutation may trigger nonsense-mediated mRNA decay. Analysis of metaphase in patient cells showed a reduction in premature sister chromatid separation compared to controls, although karyotypes were normal and there were no significant aneuploidies. Mullegama et al. (2017) postulated a loss-of-function mechanism causing haploinsufficiency, and noted that some of the other functions of STAG2, such as the regulation of gene expression, may also be disrupted by the mutation.
Holoprosencephaly 13, X-linked
In a 2-year-old girl (patient 2) with X-linked semilobar holoprosencephaly-13 (HPE13; 301043), Kruszka et al. (2019) identified a de novo heterozygous R69X mutation in the STAG2 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies in patient cells were not performed, but the variant was predicted to result in haploinsufficiency. X-inactivation studies were consistent with random X inactivation, supporting haploinsufficiency as a pathogenic mechanism. The authors noted that the patient (patient 1) with MKMS reported by Mullegama et al. (2017) had less severe midline brain anomalies, including dysgenesis of the splenium of the corpus callosum.
In 5 affected males from a large Brazilian family with Mullegama-Klein-Martinez syndrome (MKMS; 301022), Soardi et al. (2017) identified a hemizygous c.980G-A transition (c.980G-A, NM_001042749.1) in the STAG2 gene, resulting in a ser327-to-asn (S327N) substitution at a highly conserved residue important for binding to SCC1 (606462) and cohesin regulators. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. There were at least 2 confirmed healthy female carriers of the mutation. The variant was not found in the ExAC database or in 500 Brazilian controls. Analysis of patient fibroblasts showed that the mutant protein was expressed in normal amounts and localized properly to the nucleus, similar to wildtype, and there were no defects in sister chromatid cohesion. However, patient cells showed cell cycle abnormalities, including increased percentage of G2/M cells and upregulation of genes involved in cell division, mitotic regulation, and DNA replication compared to controls. These findings were consistent with a defect in transcriptional regulation. Expression of the mutation in HeLa cells showed decreased binding of the mutant protein to SCC1 and other cohesin regulators.
In a 4-year-old boy with Mullegama-Klein-Martinez syndrome (MKMS; 301022), Mullegama et al. (2019) identified a de novo heterozygous c.3027A-T transversion (NC_000023.10) in exon 27 of the STAG2 gene, resulting in a lys1009-to-asn (K1009N) substitution at a conserved residue at the end of the GR functional domain. The mutation, which was found by exome sequencing, was not found in the 1000 Genomes Project, ExAC, or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In a 4-year-old girl (patient 8) with Mullegama-Klein-Martinez syndrome (MKMS; 301022), Yuan et al. (2019) identified a de novo heterozygous c.1605T-A transversion (c.1605T-A, NM_006603.4) in the STAG2 gene, resulting in a cys535-to-ter (C535X) substitution. The mutation, which was found by exome sequencing of a large cohort of patients, was not found in the Exome Sequencing Project or ExAC databases. Functional studies of the variant and studies of patient cells were not performed, but Yuan et al. (2019) postulated a loss-of-function effect with haploinsufficiency.
In an 11-year-old girl (patient 9) with Mullegama-Klein-Martinez syndrome (MKMS; 301022), Yuan et al. (2019) identified a de novo heterozygous c.1811G-A transition (c.1811G-A, NM_006603.4) in the STAG2 gene, resulting in an arg604-to-gln (R604Q) substitution. The mutation, which was found by exome sequencing of a large cohort of patients, was not found in the Exome Sequencing Project or ExAC databases. Functional studies of the variant and studies of patient cells were not performed, but Yuan et al. (2019) postulated a loss-of-function effect with haploinsufficiency.
In a 5-year-old boy (patient 11) with Mullegama-Klein-Martinez syndrome (MKMS; 301022), Yuan et al. (2019) identified a de novo hemizygous c.476A-G transition (c.476A-G, NM_006603.4) in the STAG2 gene, resulting in a tyr159-to-cys (Y159C) substitution in the STAG domain. The mutation, which was found by exome sequencing of a large cohort of patients, was not found in the Exome Sequencing Project or ExAC databases. Functional studies of the variant and studies of patient cells were not performed, but Yuan et al. (2019) postulated a loss-of-function effect.
This variant, previously titled HOLOPROSENCEPHALY 13, X-LINKED, has been reclassified because the article on which it was based was retracted.
The article by Aoi et al. (2019) describing an arg1003-to-ter (R1003X) mutation in a male fetus (patient 1) with X-linked holoprosencephaly-13 (HPE13; 301043) was retracted. The authors had concluded that hemizygous truncating mutations cause a severe fetal phenotype and/or embryonic lethality in males, but patient 1 was in fact female.
This variant, previously titled MULLEGAMA-KLEIN-MARTINEZ SYNDROME, has been reclassified because the article on which it was based was retracted.
Aoi et al. (2019) reported a girl (patient 2) with Mullegama-Klein-Martinez syndrome (MKMS; 301022) who had a de novo trp743-to-ter (W743X) substitution in the STAG2 gene. The article was retracted because of a critical error in the reported data; see 300826.0007.
In a newborn girl (patient 1) with X-linked alobar holoprosencephaly-13 (HPE13; 301043), Kruszka et al. (2019) identified a de novo heterozygous c.3034C-T transition (chrX.123,217,380C-T, GRCh37) in the STAG2 gene, resulting in an arg1012-to-ter (R1012X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency.
In a 32-week-old female fetus (patient 3) with X-linked alobar holoprosencephaly-13 (HPE13; 301043), Kruszka et al. (2019) identified a heterozygous, likely de novo, c.436C-T transition (chrX.123,176,469C-T, GRCh37) in the STAG2 gene, resulting in an arg146-to-ter (R146X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in haploinsufficiency.
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