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ESCO2
establishment of sister chromatid cohesion N-acetyltransferase 2
The ESCO2 gene provides instructions for a protein crucial for maintaining sister chromatid cohesion, a vital process for accurate chromosome segregation during cell division. The ESCO2 gene encodes a protein essential for the proper separation of chromosomes as cells divide.
ESCO2 is located on the short (p) arm of chromosome 8, at band 8p21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The ESCO2 gene, formally known as establishment of sister chromatid cohesion N-acetyltransferase 2, is fundamental for accurate cell division. It produces a protein that is critical for the correct segregation of chromosomes into daughter cells. Understanding ESCO2's role is important for comprehending the genetic basis of conditions arising from chromosomal abnormalities.
Dysfunction of the ESCO2 protein can lead to severe developmental issues, highlighting its significance in early development and cellular processes.
What the gene does
The ESCO2 protein is an N-acetyltransferase that plays a pivotal role in establishing sister chromatid cohesion. Before a cell divides, its DNA is replicated, forming two identical copies known as sister chromatids. These chromatids must remain attached to each other until they are correctly aligned and ready to be pulled apart into new daughter cells.
The ESCO2 protein is involved in creating the 'glue' that holds these sister chromatids together. This cohesion ensures that each new cell receives a complete and accurate set of chromosomes. Without functional ESCO2, this cohesion is impaired, leading to premature separation or incorrect distribution of chromosomes, which can have significant consequences for cellular function and organismal development.
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Chromosome location
The ESCO2 gene is located on the short arm of chromosome 8 at position 8p21.1. Chromosome 8 is one of the 23 pairs of chromosomes in humans. The specific band 8p21.1 refers to a precise region on this chromosome where the ESCO2 gene resides, influencing its genetic context and potential interactions with neighbouring genes.
Protein structure
The ESCO2 protein consists of 601 amino acids. Its structure includes several distinct regions. There are two identified disordered regions: one spanning amino acids 222-243 and another from amino acids 282-315. Additionally, the protein contains a CCHH-type zinc finger domain located between amino acids 387-411. These structural elements contribute to the protein's function in establishing sister chromatid cohesion.
Key variants
Variants within the ESCO2 gene can alter the protein's structure or function, impacting its ability to maintain sister chromatid cohesion. These genetic changes can range from single amino acid substitutions to larger deletions or insertions, potentially leading to a non-functional or abnormally short protein. The specific effect of a variant depends on its location and the nature of the change.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1131+1G>T | - | Pathogenic | ★★☆☆ | Roberts-SC phocomelia syndrome |
c.118_119del | p.Asn39_Ser40insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Roberts-SC phocomelia syndrome |
c.1225C>T | p.Gln409Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Roberts-SC phocomelia syndrome |
c.1432del | p.Thr478fs | Pathogenic/Likely pathogenic | ★★☆☆ | Juberg-Hayward syndrome |
c.1475dup | p.Leu492fs | Pathogenic/Likely pathogenic | ★★☆☆ | Roberts-SC phocomelia syndrome |
c.1617G>A | p.Trp539Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ESCO2-related disorder |
c.417del | p.Lys139fs | Pathogenic | ★★☆☆ | Roberts-SC phocomelia syndrome |
c.41T>A | p.Leu14Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Roberts-SC phocomelia syndrome |
c.636dup | p.Val213fs | Pathogenic/Likely pathogenic | ★★☆☆ | Roberts-SC phocomelia syndrome |
c.648dup | p.Ser217fs | Pathogenic/Likely pathogenic | ★★☆☆ | Roberts-SC phocomelia syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the ESCO2 gene are primarily associated with Roberts syndrome. This condition is characterised by specific limb and facial abnormalities, alongside pre- and postnatal growth delays. The severity of Roberts syndrome can vary, but it often involves significant developmental challenges resulting from the impaired chromosome segregation caused by ESCO2 dysfunction.
- Roberts syndrome Dedicated page coming soon
UK clinical status
The ESCO2 gene is recognised within the NHS Genomic Medicine Service due to its clinical significance. It is listed on several PanelApp panels, including Clefting, DDG2P, Foetal anomalies (R21), Intellectual disability, Limb disorders, Radial dysplasia, Skeletal dysplasia (R104), and Structural eye disease (R36), all of which are rated 'green'. This indicates strong evidence for its association with these conditions and its inclusion in diagnostic testing pathways.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ESCO2 gene?
The ESCO2 gene provides instructions for making a protein that establishes sister chromatid cohesion. This means it helps hold replicated chromosomes (sister chromatids) together until they are ready to separate during cell division, ensuring each new cell gets the correct genetic material.
What condition is most commonly associated with ESCO2 gene variants?
Variants in the ESCO2 gene are primarily associated with Roberts syndrome. This is a rare genetic disorder characterised by limb malformations, facial abnormalities, and growth delays.
How does ESCO2 contribute to cell division?
ESCO2 acts as an N-acetyltransferase, which is crucial for creating the molecular 'glue' that binds sister chromatids together. This binding is essential for proper chromosome alignment and segregation, preventing chromosome misdistribution during cell division.
References
- Whelan G, Kreidl E, Wutz G. Cohesin acetyltransferase Esco2 is a cell viability factor and is required for cohesion in pericentric heterochromatin. The EMBO journal. 2012. PMID: 22101327
- Vega H, Trainer AH, Gordillo M. Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome. Journal of medical genetics. 2010. PMID: 19574259
- Gordillo M, Vega H, Trainer AH. The molecular mechanism underlying Roberts syndrome involves loss of ESCO2 acetyltransferase activity. Human molecular genetics. 2008. PMID: 18411254
- McNairn AJ, Gerton JL. Cohesinopathies: One ring, many obligations. Mutation research. 2008. PMID: 18786550
- Dorsett D. Roles of the sister chromatid cohesion apparatus in gene expression, development, and human syndromes. Chromosoma. 2007. PMID: 16819604
- Resta N, Susca FC, Di Giacomo MC. A homozygous frameshift mutation in the ESCO2 gene: evidence of intertissue and interindividual variation in Nmd efficiency. Journal of cellular physiology. 2006. PMID: 16775838
- Vega H, Waisfisz Q, Gordillo M. Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nature genetics. 2005. PMID: 15821733
- Hou F, Zou H. Two human orthologues of Eco1/Ctf7 acetyltransferases are both required for proper sister-chromatid cohesion. Molecular biology of the cell. 2005. PMID: 15958495
- Schüle B, Oviedo A, Johnston K. Inactivating mutations in ESCO2 cause SC phocomelia and Roberts syndrome: no phenotype-genotype correlation. American journal of human genetics. 2005. PMID: 16380922
- Adam MP, Bick S, Mirzaa GM. ESCO2 Spectrum Disorder. 1993. PMID: 20301332