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ERCC6
ERCC excision repair 6, chromatin remodeling factor
The ERCC6 gene provides instructions for producing the Cockayne Syndrome B (CSB) protein, which is crucial for DNA repair, particularly within actively transcribed genes, and plays a role in gene transcription. The ERCC6 gene encodes the Cockayne Syndrome B (CSB) protein, a vital component of the cell's DNA repair machinery.
ERCC6 is located on the long (q) arm of chromosome 10, at band 10q11.23. Arm ratio per GRCh38 - banding schematic.
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Overview
The ERCC6 gene, also known as ERCC excision repair 6, chromatin remodelling factor, contains the instructions for making a protein called Cockayne Syndrome B (CSB). This protein is integral to maintaining genomic integrity by participating in DNA repair mechanisms and assisting with gene transcription. The ERCC6 gene is primarily associated with Cockayne syndrome, an inherited condition affecting development and sensitivity to sunlight.
What the gene does
The CSB protein, encoded by the ERCC6 gene, plays a critical role in the repair of damaged DNA, particularly within genes that are actively undergoing transcription. DNA can sustain damage from various sources, including ultraviolet (UV) radiation, environmental toxins, and unstable molecules. While cells possess multiple DNA repair pathways, the CSB protein is specifically involved in transcription-coupled nucleotide excision repair. When DNA damage occurs in an active gene, the RNA polymerase enzyme, which is responsible for transcription, can become stalled. The CSB protein is thought to help remove the stalled RNA polymerase, allowing the damaged DNA segment to be repaired. It may also aid in restarting gene transcription once the repair process is complete, ensuring proper protein production.
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Chromosome location
The ERCC6 gene is located on chromosome 10 at position 10q11.23. This region of the chromosome contains the genetic information necessary for producing the CSB protein. The gene's specific location helps geneticists understand its genomic context and its potential interactions with neighbouring genes.
Protein structure
The ERCC6 protein consists of 1061 amino acids. Several regions within the protein are characterised as disordered, indicating areas that lack a fixed three-dimensional structure and can adopt various conformations. These include disordered regions at amino acids 1-39, 287-323, 344-466, 494-521, and 537-573. Such flexibility is often important for protein-protein interactions and adaptability in cellular processes.
Key variants
Variants in the ERCC6 gene can lead to alterations in the structure or function of the CSB protein. These changes can impair the protein's ability to effectively repair DNA damage or participate in transcription. Over 60 different pathogenic variants in the ERCC6 gene have been identified, primarily associated with Cockayne syndrome. The specific effect of a variant depends on its nature and location within the gene.
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.1040del | p.Gly347fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cockayne syndrome type 2 |
c.1066G>T | p.Glu356Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ERCC6-related disorder |
c.1100_1101del | p.Asp366_Ser367insTer | Pathogenic | ★★☆☆ | DE SANCTIS-CACCHIONE SYNDROME |
c.1431_1432del | p.Lys478fs | Pathogenic | ★★☆☆ | Cockayne syndrome |
c.145del | p.Ser49fs | Pathogenic | ★★☆☆ | Cockayne spectrum with or without cerebrooculofacioskeletal syndrome |
c.1717_1720del | p.Cys573fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 1 |
c.1738C>T | p.Gln580Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 1 |
c.3259C>T | p.Arg1087Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cockayne syndrome type 2 |
c.3500del | p.Ala1167fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cockayne syndrome type 2 |
c.439dup | p.Leu147fs | Pathogenic | ★★☆☆ | ERCC6-related disorder |
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 ERCC6 gene are associated with inherited conditions such as Cockayne syndrome. This rare, autosomal recessive disorder can manifest with features including microcephaly, severely delayed growth, developmental delays, and heightened sensitivity to sunlight. Additionally, certain ERCC6 variants have been linked to UV-sensitive syndrome, characterised by extreme photosensitivity and skin pigmentation changes, and age-related macular degeneration.
Inheritance pattern
Conditions caused by pathogenic ERCC6 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 ERCC6 gene is included in several NHS Genomic Medicine Service national testing panels, reflecting its clinical significance within the UK. It is featured on panels for Arthrogryposis, Bilateral congenital or childhood onset cataracts, DDG2P, Foetal anomalies, Hereditary neuropathy, Hereditary neuropathy or pain disorder, 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 (R227).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ERCC6 gene?
The ERCC6 gene provides instructions for the Cockayne Syndrome B (CSB) protein, which is essential for repairing damaged DNA, especially within actively transcribed genes. It also plays a role in the process of gene transcription.
Which conditions are associated with variants in the ERCC6 gene?
Variants in the ERCC6 gene are primarily associated with Cockayne syndrome, an inherited disorder affecting development and leading to increased sensitivity to sunlight. Some variants are also linked to UV-sensitive syndrome and age-related macular degeneration.
How is Cockayne syndrome inherited?
Cockayne syndrome, linked to the ERCC6 gene, is inherited in an autosomal recessive pattern. This means that an individual must inherit two copies of the altered gene, one from each parent, to develop the condition.
References
- Wilson BT, Lochan A, Stark Z. Novel missense mutations in a conserved loop between ERCC6 (CSB) helicase motifs V and VI: Insights into Cockayne syndrome. American journal of medical genetics. Part A. 2016. PMID: 26749132
- Laugel V. Cockayne syndrome: the expanding clinical and mutational spectrum. Mechanisms of ageing and development. 2013. PMID: 23428416
- Vélez-Cruz R, Egly JM. Cockayne syndrome group B (CSB) protein: at the crossroads of transcriptional networks. Mechanisms of ageing and development. 2013. PMID: 23562425
- 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
- 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
- Newman JC, Bailey AD, Weiner AM. Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling. Proceedings of the National Academy of Sciences of the United States of America. 2006. PMID: 16772382
- Horibata K, Iwamoto Y, Kuraoka I. Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2004. PMID: 15486090
- Licht CL, Stevnsner T, Bohr VA. Cockayne syndrome group B cellular and biochemical functions. American journal of human genetics. 2003. PMID: 14639525
- Adam MP, Bick S, Mirzaa GM. Cockayne Syndrome. 1993. PMID: 20301516