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ESCO2
establishment of sister chromatid cohesion N-acetyltransferase 2
The ESCO2 gene provides instructions for a protein crucial in maintaining sister chromatid cohesion during cell division, and pathogenic variants are associated with Roberts syndrome. The ESCO2 gene encodes a protein called establishment of sister chromatid cohesion N-acetyltransferase 2, which is vital for the proper segregation of chromosomes when 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, plays a fundamental role in cell division. It provides the genetic blueprint for a protein that is essential for ensuring chromosomes are correctly organised and separated into daughter cells.
Errors in this process can have significant consequences for development, and the ESCO2 gene is associated with conditions like Roberts syndrome, which affects limb and facial development.
What the gene does
The ESCO2 protein is critical for establishing cohesion between sister chromatids following DNA replication. Before a cell divides, its DNA is copied, resulting in two identical sister chromatids for each chromosome. The ESCO2 protein acts to create a 'glue' that holds these sister chromatids together. This cohesion is crucial for the accurate alignment and subsequent separation of chromosomes during mitosis.
Without proper ESCO2 function, sister chromatids may separate prematurely or irregularly, leading to an incorrect distribution of genetic material into daughter cells. This disruption of chromosome segregation is a hallmark of many genetic disorders and can impact cell viability and tissue development.
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Chromosome location
The ESCO2 gene is located on the short (p) arm of chromosome 8, specifically at position 8p21.1. This region denotes its precise genomic address within the human genome. The gene spans several thousands of base pairs and directs the synthesis of a protein comprising 601 amino acids.
Protein structure
The ESCO2 protein is 601 amino acids long. It contains several distinct regions that contribute to its function. Two notable disordered regions are found between amino acids 222-243 and 282-315. Additionally, a CCHH-type (Zinc finger) domain is present between amino acids 387-411. These domains likely play roles in protein-protein interactions or DNA binding, which are essential for its function in sister chromatid cohesion.
Key variants
Variants within the ESCO2 gene can alter the protein's structure and function, leading to impaired sister chromatid cohesion. These changes can range from single amino acid substitutions to larger deletions or insertions that affect the entire protein. The impact of a specific variant depends on its location and the extent to which it disrupts the ESCO2 protein's ability to perform its crucial role in cell division.
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.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 |
c.845_848del | p.Lys282fs | 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 severe abnormalities affecting limb and facial development, along with growth retardation before and after birth. The underlying cause of Roberts syndrome is the inability to produce functional ESCO2 protein, which leads to defective sister chromatid cohesion and subsequent developmental issues.
- Roberts syndrome Dedicated page coming soon
UK clinical status
The ESCO2 gene is part of several Green-rated panels within the NHS Genomic Medicine Service's PanelApp, indicating strong evidence for its association with specific conditions. It is included in panels related to Clefting, DDG2P, Foetal anomalies (R21), Intellectual disability, Limb disorders, Radial dysplasia, Skeletal dysplasia (R104), and Structural eye disease (R36). This highlights its clinical significance in the UK healthcare system for diagnosing a range of developmental disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ESCO2 gene?
The ESCO2 gene provides instructions for a protein that is essential for holding sister chromatids together after DNA replication, ensuring proper chromosome segregation during cell division.
What condition is associated with ESCO2 gene variants?
Pathogenic variants in the ESCO2 gene are primarily associated with Roberts syndrome, a rare genetic disorder characterised by limb and facial abnormalities and growth delays.
How does ESCO2 protein malfunction lead to health issues?
When the ESCO2 protein is not functional, sister chromatids may not stay properly joined, leading to errors in chromosome separation during cell division. This can result in abnormal cell development and lead to conditions like Roberts syndrome.
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