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ERCC4
ERCC excision repair 4, endonuclease catalytic subunit
ERCC4 is located on the short (p) arm of chromosome 16, at band 16p13.12. Arm ratio per GRCh38 - banding schematic.
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Overview
ERCC4 (ERCC excision repair 4, endonuclease catalytic subunit) encodes a protein that functions as the catalytic component of a DNA repair complex. The gene is located on chromosome 16 and produces a 916-amino-acid protein that partners with ERCC1 to excise damaged nucleotides from DNA strands. This repair process, known as nucleotide excision repair, protects cells from the harmful effects of ultraviolet radiation and various chemical agents that damage genetic material.
Pathogenic variants in ERCC4 are inherited in an autosomal recessive pattern, meaning two altered copies are required for disease manifestation. When both copies are non-functional, affected individuals may develop conditions characterised by extreme sun sensitivity, developmental abnormalities, and predisposition to malignancies at unusually young ages.
What the gene does
The ERCC4 protein functions as a structure-specific endonuclease that recognises and cleaves DNA at junctions between double-stranded and single-stranded regions. This enzymatic activity is essential for removing bulky DNA lesions caused by ultraviolet light exposure, chemotherapy agents, and environmental mutagens. The protein works exclusively as part of a heterodimer with ERCC1, forming what is commonly called the ERCC1-XPF complex (XPF being an alternative designation for ERCC4).
Within the nucleotide excision repair pathway, the ERCC4-ERCC1 complex makes the 5' incision flanking a damaged DNA segment, whilst other repair proteins cut the 3' side. The helicase-like region of ERCC4 assists in substrate recognition, whilst the nuclease domain performs the catalytic cutting. This coordinated activity allows cells to excise segments of damaged DNA, which are then replaced with newly synthesised nucleotides. Beyond nucleotide excision repair, the complex also participates in interstrand crosslink repair, a process critical for managing DNA damage that covalently links the two strands of the double helix.
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Chromosome location
ERCC4 is located on the short arm of chromosome 16 at position p13.12. This chromosomal region contains multiple genes involved in DNA repair and genomic maintenance. The gene spans a substantial genomic interval and is transcribed from the forward strand.
Protein structure
The ERCC4 protein comprises several functionally distinct regions across its 916-amino-acid length. The N-terminal half contains a helicase-like region (amino acids 1-457) that mediates DNA substrate recognition despite lacking true helicase activity. Within this region sit two leucine-zipper motifs (amino acids 233-254 and 270-298) that contribute to protein-protein interactions. A disordered region (amino acids 460-487) precedes a nuclear localisation signal (amino acids 486-491) that directs the protein into the nucleus where DNA repair occurs.
The C-terminal half houses the catalytic machinery. A nuclease region (amino acids 658-813) contains the conserved ERCC4 domain (amino acids 683-763), which provides the enzymatic activity for DNA strand incision. Embedded within the nuclease region is another disordered segment (amino acids 660-679). The extreme C-terminus features a helix-hairpin-helix motif (HhH2, amino acids 837-905) that mediates dimerisation with the ERCC1 partner protein, an interaction essential for enzymatic function.
Key variants
Pathogenic variants in ERCC4 disrupt the protein's ability to incise damaged DNA, leading to accumulation of unrepaired lesions. Most disease-causing changes are loss-of-function variants that eliminate nuclease activity or prevent stable complex formation with ERCC1. Because ERCC4-related conditions follow autosomal recessive inheritance, individuals typically carry two pathogenic variants, one inherited from each parent.
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.1197_1198insCA | p.Ala400fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cockayne syndrome |
c.1349G>A | p.Trp450Ter | Pathogenic/Likely pathogenic | ★★☆☆ | XFE progeroid syndrome |
c.1376C>A | p.Ser459Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Xeroderma pigmentosum, group F |
c.1402del | p.Arg468fs | Pathogenic/Likely pathogenic | ★★☆☆ | XFE progeroid syndrome |
c.1417dup | p.Gln473fs | Pathogenic/Likely pathogenic | ★★☆☆ | Xeroderma pigmentosum, group F |
c.1882_1885del | p.Glu628fs | Pathogenic/Likely pathogenic | ★★☆☆ | Xeroderma pigmentosum, group F |
c.2314C>T | p.Arg772Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Xeroderma pigmentosum, group F |
c.557_558del | p.Phe186fs | Pathogenic/Likely pathogenic | ★★☆☆ | Cockayne syndrome |
c.579G>A | p.Trp193Ter | Pathogenic | ★★☆☆ | Cockayne syndrome |
c.938dup | p.Arg314fs | Pathogenic/Likely pathogenic | ★★☆☆ | XFE progeroid syndrome |
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
Biallelic pathogenic variants in ERCC4 cause a spectrum of DNA repair disorders with overlapping clinical features. The most recognised presentation is xeroderma pigmentosum, characterised by extreme sun sensitivity, freckling in sun-exposed areas before age two, and dramatically elevated risk of skin cancers including melanoma and squamous cell carcinoma. Some individuals develop neurological degeneration. A subset of affected individuals present instead with features of Fanconi anaemia, including progressive bone marrow failure, skeletal abnormalities (particularly radial ray defects), short stature, and predisposition to haematological malignancies. The clinical presentation depends partly on the specific variants inherited and their impact on different DNA repair pathways.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ERCC4 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
ERCC4 appears on numerous UK NHS Genomic Medicine Service gene panels, reflecting its role in multiple clinical presentations. The gene holds green (high-evidence) status on panels including Xeroderma pigmentosum, Trichothiodystrophy or Cockayne syndrome, Confirmed Fanconi anaemia or Bloom syndrome, and multiple cancer susceptibility panels covering adult solid tumours, childhood solid tumours, and haematological malignancies. Additional green ratings appear on panels for radial dysplasia, severe microcephaly, cytopenias and congenital anaemias, and pigmentary skin disorders, reflecting the diverse developmental and haematological manifestations of ERCC4 deficiency.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ERCC4 gene do?
ERCC4 provides instructions for making a nuclease enzyme that cuts out damaged segments of DNA. The protein works together with ERCC1 to remove DNA lesions caused by ultraviolet light and chemical agents, helping to prevent mutations that could lead to cancer or interfere with normal cell function.
How are ERCC4 variants inherited?
ERCC4-related conditions follow autosomal recessive inheritance, meaning an affected individual inherits one pathogenic variant from each parent. Parents who each carry one variant typically have no symptoms themselves but have a 25% chance with each pregnancy of having an affected child.
Why is ERCC4 on multiple NHS gene panels?
ERCC4 variants can cause different clinical presentations depending on which DNA repair pathways are most affected. This includes extreme sun sensitivity and skin cancer risk (xeroderma pigmentosum), bone marrow failure and developmental abnormalities (Fanconi anaemia), and various combinations of these features, explaining the gene's presence across cancer, developmental, and haematological disorder panels.