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ERCC2
ERCC excision repair 2, TFIIH core complex helicase subunit
The ERCC2 gene encodes the XPD protein, an essential component of the TFIIH complex involved in DNA repair and gene transcription, with variants linked to conditions like Xeroderma pigmentosum. The ERCC2 gene is responsible for producing the XPD protein, a vital subunit of the 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, also known as excision repair cross-complementation group 2, provides the genetic blueprint for the XPD protein. This protein is a key constituent of the general transcription factor II H (TFIIH) complex, which performs two fundamental cellular processes: gene transcription and nucleotide excision repair (NER) of DNA.
Disruptions to the ERCC2 gene's function, often due to inherited pathogenic variants, are implicated in various genetic disorders, including Xeroderma pigmentosum and Trichothiodystrophy, which underscore the protein's importance in maintaining genomic integrity and proper cellular function.
What the gene does
The XPD protein, encoded by the ERCC2 gene, acts as a helicase and is an integral part of the TFIIH complex. This complex plays a crucial role in gene transcription by helping to initiate the process, thereby regulating the expression of numerous genes. The XPD protein also helps stabilise the overall TFIIH complex structure.
Beyond transcription, the TFIIH complex is central to nucleotide excision repair, a primary mechanism cells use to correct DNA damage caused by environmental factors like UV radiation and toxic chemicals. Within NER, the XPD protein uses its helicase activity to temporarily unwind the DNA double helix at the site of damage. This unwinding exposes the damaged DNA segment, allowing other repair proteins to excise and replace the incorrect sequence, thus preserving genomic stability.
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Chromosome location
The ERCC2 gene is situated on chromosome 19, specifically at band 19q13.32. This precise location on the long arm of chromosome 19 positions it within a region known to harbour genes critical for various cellular functions. The gene provides instructions for a protein that is 760 amino acids in length.
Protein structure
The ERCC2 protein, XPD, is composed of several functional regions essential for its role in the TFIIH complex. It contains a Helicase ATP-binding domain located between amino acids 7 and 283, which is critical for its ATPase activity. A DEAH box motif, spanning amino acids 234-237, is also present and is characteristic of helicase enzymes. A specific region between amino acids 438 and 637 mediates interaction with the MMS19 protein. Furthermore, a Nuclear localization signal motif is found from amino acids 682-695, directing the protein to the cell nucleus where DNA repair and transcription occur.
Key variants
Variants within the ERCC2 gene can lead to alterations in the XPD protein, affecting its ability to perform its essential functions in DNA repair and gene transcription. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, and their impact can vary from benign to pathogenic, depending on the specific change and its location within the gene. Understanding these variants is crucial for diagnosing 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.1051C>T | p.Gln351Ter | Pathogenic | ★★☆☆ | ERCC2-related disorder |
c.1187dup | p.Leu397fs | Pathogenic/Likely pathogenic | ★★☆☆ | ERCC2-related disorder |
c.1532G>A | p.Arg511Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Xeroderma pigmentosum, group D |
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 | ★★☆☆ | ERCC2-related disorder |
c.2068_2069dup | p.Lys692fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cerebrooculofacioskeletal syndrome 2 |
c.362dup | p.Thr122fs | Pathogenic/Likely pathogenic | ★★☆☆ | ERCC2-related disorder |
c.566G>A | p.Trp189Ter | 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 primarily associated with conditions such as Xeroderma pigmentosum and Trichothiodystrophy. Xeroderma pigmentosum is characterised by extreme sensitivity to UV light, leading to significant skin and eye issues. Trichothiodystrophy affects multiple body systems, notably causing brittle hair and developmental issues. Rarely, individuals may present with features of both conditions, a complex known as xeroderma pigmentosum/trichothiodystrophy (XP/TTD) complex, highlighting the critical role of ERCC2 in maintaining cellular health.
- 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
In the UK, the ERCC2 gene is recognised on several NHS Genomic Medicine Service national test panels. It is included in panels for adult solid tumours cancer susceptibility, childhood solid tumours, and childhood solid tumours cancer susceptibility. Furthermore, ERCC2 is part of panels for conditions like Bilateral congenital or childhood onset cataracts (R31), Foetal anomalies (R21), Intellectual disability, and Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome (R227), indicating its clinical significance across a range of disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ERCC2 gene?
The ERCC2 gene provides instructions for the XPD protein, which is a critical component of the TFIIH complex. This complex is involved in two main cellular processes: repairing damaged DNA through nucleotide excision repair and initiating gene transcription to regulate gene activity.
Which 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, which affects multiple body systems and causes brittle hair. Some individuals may also present with a combination of features from both conditions.
How does the XPD protein help repair DNA?
The XPD protein acts as a helicase within the TFIIH complex. It unwinds the DNA double helix at sites of damage, exposing the faulty segment. This allows other repair proteins to remove the damaged section and replace it with correct DNA, thus restoring the genetic code.
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