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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, a key component in cellular DNA repair mechanisms, particularly in active genes. The ERCC8 gene encodes the Cockayne syndrome A (CSA) protein, which plays a vital role in repairing damaged DNA within cells.
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 ERCC excision repair 8, CSA ubiquitin ligase complex subunit, is fundamental for DNA repair processes within the human body. This gene provides the genetic blueprint for a protein that aids in correcting DNA damage, which can arise from various environmental factors including UV radiation, toxic chemicals, and free radicals. Effective functioning of the ERCC8 gene is crucial to prevent DNA damage accumulation, which might otherwise lead to cellular dysfunction or cell death.
What the gene does
The ERCC8 gene is responsible for producing the Cockayne syndrome A (CSA) protein, a critical element in DNA repair. This protein primarily functions in pathways that mend DNA damage specifically within actively transcribed genes. Such damage can disrupt the cellular machinery involved in gene transcription, which is the initial step in producing proteins. While the exact molecular contributions of the CSA protein in this process are still being clarified, it is known to interact with other proteins to locate and target damaged DNA regions. By assisting in the repair of these lesions, the ERCC8 gene supports the continuous and accurate operation of cellular processes and helps maintain genomic stability.
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Chromosome location
The ERCC8 gene is situated on chromosome 5, at position 5q12.1. This specific genomic address identifies the gene's physical placement within the human genome, serving as a reference for genetic investigations and diagnostic evaluations.
Protein structure
The ERCC8 protein comprises 396 amino acids and includes several WD (tryptophan-aspartate) repeat domains. These domains are designated as 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). Additionally, the protein features a disordered region from amino acids 371-396, which may contribute to its flexibility and interactions with other molecules.
Key variants
Variants within the ERCC8 gene can impact the structure and functionality of the CSA protein, thereby affecting its capacity for DNA repair. Researchers have identified more than 30 variants in the ERCC8 gene that can cause Cockayne syndrome. These changes typically result in a CSA protein that is either non-functional or improperly structured, impairing the cell's ability to repair DNA.
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 | ★★☆☆ | Cockayne syndrome type 1 |
c.840_841del | p.Leu281fs | Pathogenic | ★★☆☆ | Cockayne syndrome type 1 |
c.966C>G | p.Tyr322Ter | Pathogenic | ★★☆☆ | See cases |
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 predominantly associated with autosomal recessive conditions such as Cockayne syndrome and Cockayne syndrome type A. Cockayne syndrome is characterised by several features, including an unusually small head size (microcephaly), extremely slow growth leading to short stature, delayed development, and heightened sensitivity to UV radiation. At least one pathogenic variant in ERCC8 has been associated with UV-sensitive syndrome, a condition in which affected individuals sunburn easily and may develop unusual skin pigmentation patterns including freckling.
- 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 panels within the UK's National Genomic Test Directory, as listed on PanelApp. It features in panels for Arthrogryposis, Bilateral congenital or childhood onset cataracts, Foetal anomalies, Hereditary neuropathy, Inherited white matter disorders, 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 function of the ERCC8 gene?
The ERCC8 gene provides instructions for the Cockayne syndrome A (CSA) protein, which is essential for repairing damaged DNA, particularly within actively transcribed genes. This helps to prevent the accumulation of DNA damage in cells.
Which conditions are associated with variants in the ERCC8 gene?
Variants in the ERCC8 gene are primarily associated with Cockayne syndrome and Cockayne syndrome type A. These conditions can cause developmental delays, growth impairment, and increased sensitivity to sunlight.
How is ERCC8 gene inheritance typically passed down?
Variants in the ERCC8 gene are typically inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the altered gene (one from each parent) to develop an associated condition.
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