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ERCC2
ERCC excision repair 2, TFIIH core complex helicase subunit
The ERCC2 gene provides instructions for the XPD protein, a key component of the TFIIH complex involved in DNA repair and gene transcription. The ERCC2 gene encodes the XPD protein, an essential subunit of the general transcription factor IIH (TFIIH) complex.
ERCC2 is located on the long (q) arm of chromosome 19, at band 19q13.32. Arm ratio per GRCh38 - banding schematic.
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Overview
The ERCC2 gene provides the genetic blueprint for the XPD protein, which is an integral part of the TFIIH complex. This complex is crucial for two fundamental cellular processes: gene transcription, the initial step in protein production, and DNA repair. Through its involvement in the TFIIH complex, the ERCC2 gene helps regulate the expression of many genes and ensures the integrity of the genome by fixing damaged DNA.
Damage to DNA can arise from various sources, including ultraviolet (UV) radiation from sunlight and exposure to toxic chemicals. The XPD protein, encoded by ERCC2, is particularly important in the nucleotide excision repair (NER) pathway, a primary mechanism cells use to correct DNA lesions before they can cause cellular problems.
What the gene does
The XPD protein, produced from the ERCC2 gene, functions as a helicase within the TFIIH complex. Helicases are enzymes that bind to specific regions of DNA and temporarily unwind its double-stranded structure. This unwinding action is critical for both gene transcription and DNA repair processes. In gene transcription, the TFIIH complex, stabilised by the XPD protein, helps initiate the process by unwinding DNA to allow RNA polymerase access to the genetic code.
In DNA repair, particularly via the nucleotide excision repair (NER) pathway, the XPD helicase unwinds the DNA helix around a damaged site. This exposes the damaged nucleotides, allowing other proteins to excise the faulty section. The gap is then filled with correct DNA, restoring the original sequence. The XPD protein also appears to work in concert with the XPB protein, encoded by the ERCC3 gene, to facilitate the initiation of gene transcription.
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Chromosome location
The ERCC2 gene is situated on chromosome 19, specifically at position 19q13.32. This location refers to the long (q) arm of chromosome 19, within region 1, band 3, and sub-band 32. The protein it encodes consists of 760 amino acids.
Protein structure
The ERCC2 protein, also known as XPD, is composed of 760 amino acids and features several distinct functional regions. It contains a Helicase ATP-binding domain spanning amino acids 7-283, which is essential for its helicase activity. A key motif within this domain is the DEAH box, located at amino acids 234-237, which is characteristic of a family of helicases. A region between amino acids 438-637 mediates interaction with MMS19, indicating its role in protein complex formation. Additionally, a Nuclear localisation signal is found between amino acids 682-695, guiding the protein to its correct cellular compartment.
Key variants
Variants within the ERCC2 gene can alter the structure or function of the XPD protein, affecting its ability to participate in DNA repair and gene transcription. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, and their impact varies depending on the specific alteration and its location within the gene. Such variants can disrupt the precise mechanisms by which the XPD protein unwinds DNA or interacts with other components of the TFIIH complex.
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.1187dup | p.Leu397fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 2 |
c.1532G>A | p.Arg511Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 2 |
c.1666-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 2 |
c.1847_1850del | p.Arg616fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 2 |
c.1888_1889del | p.Ser630fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 2 |
c.1912G>T | p.Glu638Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 2 |
c.2068_2069dup | p.Lys692fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 2 |
c.566G>A | p.Trp189Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 2 |
c.570C>A | p.Cys190Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 2 |
c.778C>T | p.Gln260Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal 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 ERCC2 gene are associated with several inherited conditions, primarily affecting DNA repair mechanisms. One such condition is Xeroderma pigmentosum, an autosomal recessive disorder characterised by extreme sensitivity to UV light and a significantly increased risk of skin cancer. ERCC2 variants can also cause trichothiodystrophy, a multi-system disorder often presenting with brittle hair, developmental delays, and sensitivity to sunlight. In some rare cases, variants can lead to a complex presentation with features of both conditions, known as xeroderma pigmentosum/trichothiodystrophy complex.
- Xeroderma pigmentosum Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ERCC2 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 ERCC2 gene is included in several NHS Genomic Medicine Service national testing panels, reflecting its clinical significance within the UK. It is assessed for adult solid tumours cancer susceptibility, bilateral congenital or childhood onset cataracts, childhood solid tumours, and childhood solid tumours cancer susceptibility. Furthermore, ERCC2 is part of the DDG2P panel, the Foetal anomalies (R21) panel, the Intellectual disability panel, and the Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome (R227) panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the ERCC2 gene?
The ERCC2 gene provides instructions for the XPD protein, which is a crucial part of the TFIIH complex. This complex is vital for both initiating gene transcription and repairing damaged DNA, especially through the nucleotide excision repair pathway.
What conditions are associated with ERCC2 gene variants?
Variants in the ERCC2 gene are primarily associated with Xeroderma pigmentosum, a condition causing extreme sensitivity to UV light, and trichothiodystrophy, a multi-system disorder often characterised by brittle hair and developmental issues. Some individuals may present with a combination of features from both conditions.
How does the XPD protein repair DNA?
As a helicase, the XPD protein unwinds the double helix of DNA around a damaged site. This action exposes the damaged section, allowing other proteins to remove it and replace it with the correct DNA sequence, thereby repairing the genetic material.
References
- Oksenych V, Coin F. The long unwinding road: XPB and XPD helicases in damaged DNA opening. Cell cycle (Georgetown, Tex.). 2010. PMID: 20016270
- Boyle J, Ueda T, Oh KS. Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy. Human mutation. 2008. PMID: 18470933
- Faghri S, Tamura D, Kraemer KH. Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifestations. Journal of medical genetics. 2008. PMID: 18603627
- Nishiwaki T, Kobayashi N, Iwamoto T. Comparative study of nucleotide excision repair defects between XPD-mutated fibroblasts derived from trichothiodystrophy and xeroderma pigmentosum patients. DNA repair. 2008. PMID: 18817897
- Lambert WC, Gagna CE, Lambert MW. Xeroderma pigmentosum: its overlap with trichothiodystrophy, Cockayne syndrome and other progeroid syndromes. Advances in experimental medicine and biology. 2008. PMID: 19181118
- Lehmann AR. The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes & development. 2001. PMID: 11156600
- Broughton BC, Berneburg M, Fawcett H. Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene. Human molecular genetics. 2001. PMID: 11709541