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STROMAL ANTIGEN 1; STAG1

STROMAL ANTIGEN 1; STAG1

Alternative titles; symbolsCOHESIN SUBUNIT SA1HGNC Approved Gene Symbol: STAG1Cytogenetic location: 3q22.3 Genomic coordinates (GRCh38): 3:136,336,234-136,75...

Alternative titles; symbols

  • COHESIN SUBUNIT SA1

HGNC Approved Gene Symbol: STAG1

Cytogenetic location: 3q22.3 Genomic coordinates (GRCh38): 3:136,336,234-136,752,411 (from NCBI)

▼ Description
The STAG1 gene encodes a subunit of the cohesin complex, which has a crucial role in the control of chromosome segregation during cell division. The cohesin complex also plays a role in gene transcription as well as in DNA repair and replication (summary by Lehalle et al., 2017).

▼ Cloning and Expression
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. Carramolino et al. (1997) used an antibody against stromal cell extracts to identify a mouse cDNA encoding a novel protein, which they named stromal antigen-1 (SA1). By screening a human thymus cDNA library with the mouse SA1 cDNA, Carramolino et al. (1997) isolated a cDNA encoding SA1, which was later symbolized STAG1. The deduced 1,258-amino acid protein contains an REDV sequence and potential glycosaminoglycan binding sites. The amino acid sequence of STAG1 is 98.9% and 78% similar to that of mouse SA1 and human STAG2 (300826), respectively. By Northern blot analysis, SA1 mRNA was detected in all mouse organs analyzed as well as in a mouse stromal cell line. However, using immunoprecipitation followed by immunoblotting, SA1 protein was detected only in a lymphoma cell line, in 1 of 3 stromal cell lines, and in bone marrow, thymus, and spleen. The SA1 protein was found in the nuclear but not the cytoplasmic cell compartment.

▼ Gene Function
By immunoprecipitation and immunoblot analyses, Sumara et al. (2000) showed that STAG1 is expressed as an approximately 155-kD protein that assembles with the cohesin proteins SMC1 (300040), SMC3 (606062), and SCC1 (RAD21; 606462). 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 STAG1 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 STAG2, 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.

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.

▼ Molecular Genetics
In 6 members of a family (family 5) with autosomal dominant mental retardation-47 (MRD47; 617635), Lehalle et al. (2017) identified a heterozygous intragenic deletion within the STAG1 gene (604358.0001). The deletion, which was found by array-CGH, segregated with the disorder in the family. Whole-exome sequencing of several large patient cohorts identified 11 different nonrecurrent de novo heterozygous missense or frameshift mutations in the STAG1 gene (see, e.g., 604358.0002-604358.0006) in 11 additional unrelated patients with a similar phenotype. Functional studies of the variants and studies of patient cells were not performed, but Lehalle et al. (2017) postulated that the neurodevelopmental phenotype is caused by STAG1 haploinsufficiency with a putative disruptive effect on transcriptional regulation.

▼ ALLELIC VARIANTS ( 6 Selected Examples):

.0001 MENTAL RETARDATION, AUTOSOMAL DOMINANT 47
STAG1, 173-BP DEL
In 6 members of a family (family 5) with autosomal dominant mental retardation-47 (MRD47; 617635), Lehalle et al. (2017) identified a heterozygous 173-bp intragenic deletion within the STAG1 gene including exons 2-5 or 2-6. The deletion, which was found by array-CGH, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

.0002 MENTAL RETARDATION, AUTOSOMAL DOMINANT 47
STAG1, HIS478PRO
In a patient (patient 8) with autosomal dominant mental retardation-47 (MRD47; 617635), Lehalle et al. (2017) identified a de novo heterozygous c.1433A-C transversion (c.1433A-C, NM_005862.2) in the STAG1 gene, resulting in a his478-to-pro (H478P) substitution at a conserved residue. The mutation, which was found by exome sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.

.0003 MENTAL RETARDATION, AUTOSOMAL DOMINANT 47
STAG1, ARG216GLY
In a patient (patient 9) with autosomal dominant mental retardation-47 (MRD47; 617635), Lehalle et al. (2017) identified a de novo heterozygous c.646A-G transition (c.646A-G, NM_005862.2) in the STAG1 gene, resulting in an arg216-to-gly (R216G) substitution at a conserved residue. The mutation, which was found by exome sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.

.0004 MENTAL RETARDATION, AUTOSOMAL DOMINANT 47
STAG1, ARG373GLN
In a patient (patient 10) with autosomal dominant mental retardation-47 (MRD47; 617635), Lehalle et al. (2017) identified a de novo heterozygous c.1118G-A transition (c.1118G-A, NM_005862.2) in the STAG1 gene, resulting in an arg373-to-gln (R373Q) substitution at a conserved residue. The mutation, which was found by exome sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.

.0005 MENTAL RETARDATION, AUTOSOMAL DOMINANT 47
STAG1, 5-BP DUP, NT1460
In a patient (patient 11) with autosomal dominant mental retardation-47 (MRD47; 617635), Lehalle et al. (2017) identified a de novo heterozygous 5-bp duplication (c.1460_1464dup, NM_005862.2) in the STAG1 gene, resulting in a frameshift and premature termination (Trp489ValfsTer10). The mutation, which was found by exome sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.

.0006 MENTAL RETARDATION, AUTOSOMAL DOMINANT 47
STAG1, 1-BP DUP, NT1736
In a patient (patient 16) with autosomal dominant mental retardation-47 (MRD47; 617635), Lehalle et al. (2017) identified a de novo heterozygous 1-bp duplication (c.1736dup, NM_005862.2) in the STAG1 gene, resulting in a frameshift and premature termination (Ser580ValfsTer21). The mutation, which was found by exome sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.

Tags: 3q22.3