Alternative titles; symbols
HGNC Approved Gene Symbol: ESCO2
SNOMEDCT: 48718006, 721874001;
Cytogenetic location: 8p21.1 Genomic coordinates (GRCh38) : 8:27,771,974-27,819,660 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p21.1 | Juberg-Hayward syndrome | 216100 | Autosomal recessive | 3 |
| Roberts-SC phocomelia syndrome | 268300 | Autosomal recessive | 3 |
The ESCO2 gene encodes a member of the family of acetyltransferases involved in the establishment of sister chromatid cohesion during S phase and postreplicative sister chromatid cohesion induced by double-strand breaks (Vega et al., 2005).
Using a candidate gene approach within a critical region for Roberts syndrome (RBS; 268300), Vega et al. (2005) identified the ESCO2 gene. The cDNA open reading frame of 1,806 nucleotides predicted a protein of 601 amino acids. Northern blot analysis identified a predominant mRNA of approximately 3.3 kb in all human fetal tissues tested and in adult thymus, placenta, and small intestine. Similarity to orthologs in several vertebrates indicated evolutionary conservation. The ESCO2 protein product is a member of a conserved protein family that is required for the establishment of sister chromatid cohesion during S phase and has putative acetyltransferase activity.
By searching databases for human proteins similar to yeast and fly proteins involved in sister chromatid cohesion, followed by 5-prime RACE of a fetal thymus cDNA library, Hou and Zou (2005) cloned EFO2. The C-terminal half of the deduced protein contains a C2H2 zinc finger and a putative acetyltransferase domain. Within this region, EFO2 shares 59% amino acid identity with EFO1 (ESCO1; 609674), but their N-terminal halves are dissimilar.
By in situ hybridization in the developing mouse at embryonic day 14.5, Kantaputra et al. (2021) detected expression of Esco2 in the eyelid, lip, tongue, palate, digit, and hair follicles. Esco2 expression was also observed in the long bones of the developing forelimb, but not in the hindlimb.
Vega et al. (2005) determined that the ESCO2 gene contains 11 exons spanning 30.3 kb, with the start codon in exon 2.
The ESCO2 gene maps to chromosome 8p21.1 (Strausberg et al., 2002).
Hou and Zou (2005) found that the C-terminal half of EFO2 possessed autoacetylation activity. RNA interference in HeLa cells showed that EFO2 was required for sister chromatid cohesion. There was a significant increase in mitotic cells with unpaired chromatids (65%) when EFO2 was depleted and a further increase in unpaired chromatids (93%) when both EFO1 and EFO2 were reduced simultaneously. Depletion of EFO1 or EFO2 resulted in an enrichment in G2/M cells, an increase in cells with chromosomes scattered along spindles, and an increase in cells with multipole spindles. However, depletion of EFO1 or EFO2 had no effect on the binding of cohesin (see 606462) with chromosomes in interphase cells. All cellular effects were exacerbated in cells depleted of both EFO1 and EFO2. In HeLa and 293T human embryonic kidney cells, about 70% of endogenous EFO1 and EFO2 associated with chromosomes, but the 2 proteins were differentially regulated during the cell cycle. EFO1 remained on chromosomes in mitosis, whereas EFO2 dissociated from chromosomes and/or was degraded. Mutation analysis indicated that binding of EFO1 or EFO2 to chromosomes was mediated by their diverse N termini.
Moldovan et al. (2006) found that yeast Eco1 and human ESCO2 interacted directly with PCNA (176740) via a conserved PIP box variant in their N termini. Yeast Eco1 mutants deficient in Eco1-Pcna interaction were defective in chromatid cohesion and inviable. Moldovan et al. (2006) concluded that PCNA is crucially involved in the establishment of cohesion in S phase.
Using immunoprecipitation analysis, Kim et al. (2008) showed that human ESCO2 interacted with components of the COREST corepressor complex, including COREST (RCOR; 607675). ESCO2 also interacted with various histone methyltransferases, including SUV39H1 (300254), SETDB1 (604396), and G9A (EHMT2; 604599), and the ESCO2 complex displayed histone H3 (see 602810) lys9 (H3K9) methyltransferase activity and transcription repression activity. The COREST complex, SETDB1, and SUV39H1 were required for ESCO2-mediated transcriptional repression. Furthermore, transcriptional repression by ESCO2 correlated with changes in histone tail modification, indicating that ESCO2 repressed transcription through modulation of chromatin structure.
Through single-molecule analysis, Terret et al. (2009) demonstrated that a replication complex, the RFC-CTF18 clamp loader (see 613201), controls the velocity spacing and restart activity of replication forks in human cells and is required for robust acetylation of cohesin's SMC3 subunit (606062) and sister chromatid cohesion. Unexpectedly, Terret et al. (2009) discovered that cohesin acetylation itself is a central determinant of fork processivity, as slow-moving replication forks were found in cells lacking the Eco1-related acetyltransferases ESCO1 or ESCO2 (including those derived from patients with Roberts syndrome (268300), in whom ESCO2 is biallelically mutated), and in cells expressing a form of SMC3 that cannot be acetylated. This defect was a consequence of cohesin's hyperstable interaction with 2 regulatory cofactors, WAPL (610754) and PDS5A (613200); removal of either cofactor allowed forks to progress rapidly without ESCO1, ESCO2, or RFC-CTF18. Terret et al. (2009) concluded that their results showed a novel mechanism for clamp loader-dependent fork progression, mediated by the posttranslational modification and structural remodeling of the cohesin ring. Loss of this regulatory mechanism leads to the spontaneous accrual of DNA damage and may contribute to the abnormalities of the Roberts syndrome cohesinopathy.
By in situ hybridization of human embryos, Vega et al. (2010) found expression of ESCO2 in brain, first and third branchial arches, otocyst, dorsal root ganglia, limb buds, kidney, and gonads. At Carnegie stage (CS) 14 (32 days postovulation), ESCO2 expression was detected in the neuroepithelium of the hindbrain, midbrain, telencephalic vesicle, otocyst, mandibular component of the first and third branchial arches, and developing dorsal root ganglia. At the limb buds, ESCO2 showed a homogeneous mesenchymal expression pattern. There was absence of detectable expression in the eye, surrounding vertebral body and ribs, and cardiac tissues and developing great vessels at the stages tested. At CS 17 (41 days postovulation), expression in the limbs was confined to discrete zones in the developing hand plate. At CS 21 (52 days postovulation), expression appeared confined to areas surrounding the distal tip of the cartilaginous bone of the long bones of the forearm, wrist, and phalanges and underlying the developing sternum. In kidney, expression at CS 21 was localized to the metanephric cortex and male gonadal epithelium.
Roberts-SC Phocomelia Syndrome
SC phocomelia and Roberts syndrome were initially thought to be separate disorders, with SC phocomelia being a similar but milder disorder. They are now considered to be the same entity, designated Roberts-SC phocomelia syndrome (RBS; 268300).
In 18 individuals with Roberts syndrome from 15 families of different ethnic backgrounds, Vega et al. (2005) found 8 different mutations in the ESCO2 gene. They identified 1 missense mutation at a highly conserved residue (W539G; 609353.0001), 1 nonsense mutation (R169X; 609353.0002), and 6 frameshift mutations. Vega et al. (2005) stated that RBS was the first human disorder in which a chromatid cohesion defect was shown to be associated with developmental abnormalities. Defects in chromatid cohesion lead to mitotic spindle checkpoint activation and impaired cell growth. The mitotic spindle checkpoint may be activated by the defect, resulting in the mitotic delay and impaired cell proliferation observed in RBS cells. During embryogenesis, the loss of progenitor cells could preclude a sufficient number of cells required for development of structures affected in RBS.
Schule et al. (2005) noted that heterochromatin repulsion (HR) was found to be characteristic of both Roberts syndrome and SC phocomelia and was not complemented in somatic cell hybrids, thus suggesting that the disorders were allelic. To determine whether ESCO2 mutations were also responsible for SC phocomelia, Schule et al. (2005) studied 3 families with SC and 2 families in which variable degrees of limb and craniofacial abnormalities, detected by ultrasound, led to pregnancy terminations. All cases were positive for HR. They identified 7 novel mutations in exons 3 through 8 of ESCO2. In 2 families, affected individuals were homozygous, for a 5-nucleotide deletion in 1 family and a splice site mutation in the other. In 3 nonconsanguineous families, probands were compound heterozygous for a single-nucleotide insertion or deletion, a nonsense mutation, or a splice site mutation. Abnormal splice products were characterized at the RNA level. Since only protein-truncating mutations were identified, regardless of clinical severity, Schule et al. (2005) concluded that genotype does not predict phenotype. Having established that the Roberts syndrome and SC phocomelia are caused by mutations in the same gene, Schule et al. (2005) delineated the clinical phenotype of the tetraphocomelia spectrum that is associated with HR and ESCO2 mutations, and differentiated it from other types of phocomelia that are negative for HR.
Gordillo et al. (2008) stated that Roberts syndrome and SC phocomelia are the same syndrome with varying phenotypic expression. They analyzed the ESCO2 gene in 16 RBS pedigrees with 17 affected individuals and identified 15 different mutations; 13 individuals were homozygous and 4 were compound heterozygous for the mutations. Gordillo et al. (2008) noted that all reported ESCO2 mutations associated with Roberts syndrome/SC phocomelia cause premature stop codons prior to or within the acetyltransferase domain, except for the W539G mutation. Analysis of ESCO2 mutations, including W539G, R169X, and 3 frameshift mutations (see, e.g., 609353.0003), demonstrated that the W539G mutation results in loss of autoacetyltransferase activity and a cellular phenotype that causes cohesion defects, reduction in proliferation capacity, and mitomycin C sensitivity equivalent to those produced by frameshift and nonsense mutations associated with decreased levels of mRNA and absence of protein. Gordillo et al. (2008) concluded that loss of acetyltransferase activity contributes to the pathogenesis of Roberts syndrome/SC phocomelia.
Juberg-Hayward Syndrome
In 2 Thai brothers with Juberg-Hayward syndrome (JHS; 216100), Kantaputra et al. (2020) identified homozygosity for a nonsense mutation in the ESCO2 gene (R552X; 609353.0008) that segregated with disease in the family. Cytogenetic testing revealed premature centromere separation or lack of cohesion at the centromeric heterochromatic regions in both patients.
In a 2-year-old Thai girl with Juberg-Hayward syndrome, Kantaputra et al. (2021) identified homozygosity for the R552X mutation in the ESCO2 gene.
In an analysis of 49 patients with ESCO2 mutations, including 18 previously reported cases, Vega et al. (2010) found no clear genotype/phenotype correlation. However, the presence or absence of corneal opacities segregated with specific mutations in some cases. All 7 individuals from 4 families with the 750insG mutation (609353.0003) lacked corneal opacities, whereas all 5 patients with the R169X mutation (609353.0002) had corneal opacities. In addition, patients without corneal opacities were less likely to present with cardiac abnormalities, and patients with corneal opacities were more likely to present with mental retardation. Skeletal defects were more common in patients with cleft lip/palate. Vega et al. (2010) found that both Roberts syndrome and SC phocomelia could be caused by the same mutation in different members of the same family, indicating that the 2 disorders represent a phenotypic spectrum.
In a Canadian family with Roberts-SC phocomelia syndrome (RBS; 268300) reported by Tomkins et al. (1979), Vega et al. (2005) identified a 1615T-G transversion in exon 10 of the ESCO2 gene, resulting in substitution of glycine at the highly conserved tryptophan-539 (W539G).
In 3 Colombian families, Vega et al. (2005) found that individuals with Roberts-SC phocomelia syndrome (RBS; 268300) were homozygous for a 505C-T transition in exon 3 of the ESCO2 gene, resulting in an arg169-to-ter (R169X) substitution.
In affected members of 4 Colombian families with Roberts-SC phocomelia syndrome (RBS; 268300) with a common ancestor in the 18th century, Vega et al. (2005) identified a homozygous 1-bp insertion in exon 3 of the ESCO2 gene, 750_751insG, resulting in a frameshift and premature termination (Glu251fsTer30).
Studying a lymphoblast cell line (LCL) from the proband of 1 of the original families described by Herrmann et al. (1969) as having 'SC pseudothalidomide syndrome' (RBS; 268300), Schule et al. (2005) identified compound heterozygosity for 2 mutations in the ESCO2 gene: 751_752insA, causing a frameshift and a premature stop codon (Lys253fsTer26), and 1269G-A, causing a nonsense mutation (W423X; 609353.0005) and loss of the acetyltransferase domain from the predicted protein. The mutations resided in exons 3 and 8 of the gene. This was patient 3 of Herrmann et al. (1969); an update was provided by Feingold (1992). The patient died at the age of 23 years from complications of a myocardial infarct.
For discussion of the trp423-to-ter (W423X) mutation in the ESCO2 gene that was found in compound heterozygous state in a patient with Roberts-SC phocomelia syndrome (RBS; 268300) by Schule et al. (2005), see 609353.0004.
In 2 adult sisters of German descent with Roberts-SC phocomelia syndrome (RBS; 268300) described by Parry et al. (1986), Schule et al. (2005) found compound heterozygosity for 2 mutations in exon 3 of the ESCO2 gene: 604C-T, resulting in a premature stop codon (Q202X), and a single-nucleotide deletion (752delA; 609353.0007), causing a frameshift with a predicted truncated protein (Lys253fsTer12).
For discussion of the 1-bp deletion (752delA) in the ESCO2 gene that was found in compound heterozygous state in patients with Roberts-SC phocomelia syndrome (RBS; 268300) by Schule et al. (2005), see 609353.0006.
In 2 Thai brothers from the Lisu tribe with Juberg-Hayward syndrome (JHS; 216100), Kantaputra et al. (2020) identified homozygosity for a c.1654C-T transition (c.1654C-T, NM_001017420.2) in exon 10 of the ESCO2 gene, resulting in an arg552-to-ter (R552X) substitution. Their unaffected first-cousin parents and 2 unaffected sibs were heterozygous for the mutation, which was not found in an in-house exome database of 321 individuals. The variant was present at very low frequency in the gnomAD database, appearing once in heterozygosity in the South Asian population (minor allele frequency, 0.00003 for South Asians, and 0.000004 for all of gnomAD). Analysis of transfected COS7 cells revealed a shortened 65-kD protein from cells expressing the R552X mutant, compared to the expected 80-kD protein observed from wildtype cells. Noting that the amount of mutant protein was less than 10% of that of wildtype ESCO2, the authors suggested that the shortened polypeptide chain may cause destabilization of the protein or its mRNA.
In a 2-year-old Thai girl from the Lisu tribe with Juberg-Hayward syndrome, Kantaputra et al. (2021) identified homozygosity for the R552X substitution (c.1654C-T, NM_001017420.2). Her unaffected consanguineous parents were heterozygous for the mutation, which was not present in her unaffected sister.
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