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ERCC8
ERCC excision repair 8, CSA ubiquitin ligase complex subunit
The ERCC8 gene provides instructions for the Cockayne syndrome A (CSA) protein, which plays a crucial role in repairing damaged DNA, particularly within actively expressed genes. ERCC8 encodes the CSA protein, an important component of the cellular machinery that repairs DNA.
ERCC8 is located on the long (q) arm of chromosome 5, at band 5q12.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The ERCC8 gene, also known as Cockayne syndrome A (CSA), provides the blueprint for a protein integral to DNA repair processes. This protein is essential for maintaining genomic integrity by addressing DNA damage that can arise from environmental factors such as ultraviolet (UV) radiation, toxic chemicals, and free radicals.
Effective DNA repair is vital for preventing cellular malfunction and cell death. The CSA protein specifically targets damaged DNA within genes that are actively being transcribed, although its precise mechanism in this process is still under investigation. Disruptions in ERCC8 function are linked to several inherited conditions.
What the gene does
The ERCC8 gene produces the Cockayne syndrome A (CSA) protein, which is a key player in the cellular response to DNA damage. DNA can sustain damage from various sources, including UV light, radiation, and harmful chemicals, which can impede essential cellular activities like gene transcription - the initial step in protein synthesis.
While cells possess multiple mechanisms to correct DNA damage, the CSA protein is specialised in repairing damage within genes that are actively undergoing transcription. This ensures that genetic information can be accurately read and processed. The CSA protein is known to interact with other proteins, likely to facilitate the identification and targeting of damaged DNA regions, thereby helping to prevent the accumulation of genetic errors and maintain proper cellular function.
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Chromosome location
The ERCC8 gene is located on chromosome 5, specifically at position 5q12.1. This region denotes its precise address within the long arm (q) of chromosome 5. The gene's location is consistent across individuals and is a fixed point within the human genome.
Protein structure
The ERCC8 gene encodes a protein composed of 396 amino acids. This protein features several distinct structural elements. It contains seven WD repeat domains, labelled WD 1 (amino acids 33-73), WD 2 (amino acids 88-129), WD 3 (amino acids 133-173), WD 4 (amino acids 177-216), WD 5 (amino acids 235-274), WD 6 (amino acids 281-321), and WD 7 (amino acids 325-363). These WD repeats typically facilitate protein-protein interactions. The protein also contains a disordered region at its C-terminus, spanning amino acids 371-396.
Key variants
Variants in the ERCC8 gene can affect the structure and function of the CSA protein, impairing its ability to repair DNA. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions within the gene. The clinical impact of an ERCC8 variant depends on its specific nature and location, influencing the severity and presentation of associated conditions.
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.162del | p.Glu55fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cockayne syndrome type 1 |
c.174C>A | p.Tyr58Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ERCC8-related disorder |
c.176T>C | p.Met59Thr | Pathogenic/Likely pathogenic | ★★☆☆ | UV-sensitive syndrome 2 |
c.223_227del | p.Asn75fs | Pathogenic | ★★☆☆ | UV-sensitive syndrome 2 |
c.275+1G>A | - | Pathogenic | ★★☆☆ | Cockayne syndrome |
c.427del | p.Thr143fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cockayne syndrome type 1 |
c.467_468dup | p.Cys157fs | Pathogenic/Likely pathogenic | ★★☆☆ | UV-sensitive syndrome 2 |
c.547C>T | p.Gln183Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ERCC8-related disorders |
c.840_841del | p.Leu281fs | Pathogenic | ★★☆☆ | Cockayne syndrome type 1 |
c.856A>T | p.Lys286Ter | Pathogenic/Likely pathogenic | ★★☆☆ | UV-sensitive syndrome 2 |
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 ERCC8 gene are primarily associated with Cockayne syndrome, an autosomal recessive disorder. Specifically, ERCC8 variants are known to cause Cockayne syndrome type A. This condition is characterised by features such as microcephaly (abnormally small head size), severe growth delays, developmental delays, and increased sensitivity to sunlight (photosensitivity). Additionally, some ERCC8 variants have been linked to UV-sensitive syndrome, which primarily causes extreme sensitivity to UV radiation.
- Cockayne syndrome
- Cockayne syndrome type A Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ERCC8 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The ERCC8 gene is included in several NHS Genomic Medicine Service national test panels. It is listed as 'green' on PanelApp UK for conditions such as Arthrogryposis, Bilateral congenital or childhood onset cataracts, Foetal anomalies, Hereditary neuropathy, Intellectual disability, IUGR and IGF abnormalities, Retinal disorders, Severe microcephaly, White matter disorders and cerebral calcification - childhood onset, and Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the ERCC8 gene?
The ERCC8 gene provides instructions for making the Cockayne syndrome A (CSA) protein, which is essential for repairing damaged DNA, especially within genes that are actively being used by the cell.
What is Cockayne syndrome?
Cockayne syndrome is a rare genetic disorder associated with ERCC8 variants. It can lead to symptoms such as an unusually small head, very slow growth, delayed development, and increased sensitivity to sunlight.
How does ERCC8 relate to UV sensitivity?
The ERCC8 gene's protein product helps repair DNA damage caused by UV radiation. When this protein is not functioning correctly due to certain ERCC8 variants, individuals can experience heightened sensitivity to sunlight, as seen in conditions like Cockayne syndrome and UV-sensitive syndrome.
References
- Laugel V. Cockayne syndrome: the expanding clinical and mutational spectrum. Mechanisms of ageing and development. 2013. PMID: 23428416
- Saijo M. The role of Cockayne syndrome group A (CSA) protein in transcription-coupled nucleotide excision repair. Mechanisms of ageing and development. 2013. PMID: 23571135
- Laugel V, Dalloz C, Durand M. Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome. Human mutation. 2010. PMID: 19894250
- Nardo T, Oneda R, Spivak G. A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage. Proceedings of the National Academy of Sciences of the United States of America. 2009. PMID: 19329487
- Spivak G, Hanawalt PC. Host cell reactivation of plasmids containing oxidative DNA lesions is defective in Cockayne syndrome but normal in UV-sensitive syndrome fibroblasts. DNA repair. 2006. PMID: 16129663
- Bertola DR, Cao H, Albano LMJ. Cockayne syndrome type A: novel mutations in eight typical patients. Journal of human genetics. 2006. PMID: 16865293
- Cao H, Williams C, Carter M. CKN1 (MIM 216400): mutations in Cockayne syndrome type A and a new common polymorphism. Journal of human genetics. 2004. PMID: 14661080
- Kamiuchi S, Saijo M, Citterio E. Translocation of Cockayne syndrome group A protein to the nuclear matrix: possible relevance to transcription-coupled DNA repair. Proceedings of the National Academy of Sciences of the United States of America. 2002. PMID: 11782547