ERCC2

The ERCC2 gene, also known as XPD, encodes a helicase that plays a crucial role in nucleotide excision repair (NER) and transcription regulation as part of the TFIIH complex. 

Mutations in ERCC2 disrupt DNA repair, leading to genetic disorders such as Xeroderma Pigmentosum (XP), Trichothiodystrophy (TTD), and Cockayne Syndrome (CS), as well as genomic instability in cancer, particularly bladder cancer, where ERCC2 mutations alter mutation distribution patterns and enhance sensitivity to cisplatin-based chemotherapy.

What is ERCC2 (Excision Repair Cross-Complementation Group 2)?

The ERCC2 gene, also known as XPD, is located on chromosome 19q13.3 and encodes a 761-amino acid ATP-dependent helicase, a core component of the transcription factor II H (TFIIH) complex. 

ERCC2 plays a pivotal role in nucleotide excision repair (NER), a key DNA repair pathway that removes bulky DNA lesions caused by UV radiation, chemical mutagens, and oxidative stress. 

In addition to DNA repair, ERCC2 involves transcription regulation, cell cycle control, and maintaining genomic stability.

Molecular Function

The XPD helicase is essential for multiple cellular processes, including:

• DNA Repair: Facilitates NER by unwinding damaged DNA to allow removal and replacement of altered nucleotides.
• Transcription Regulation: Interacts with RNA polymerase II and the TFIIH complex to assist in basal transcription.
• Cell Cycle Control: This enzyme regulates cyclin-dependent kinases (CDKs) through its interaction with CDK7 in the CAK (CDK-activating kinase) complex, influencing cell cycle progression.
• Protein Interactions: Contains an iron-sulfur (Fe-S) cluster domain, critical for helicase activity and responding to DNA damage.

Genetic Mutations and Associated Disorders

Mutations in ERCC2 lead to autosomal recessive syndromes, affecting both DNA repair and transcription regulation. The severity of these disorders varies based on the location and nature of the mutation.

Xeroderma Pigmentosum, Group D (XP-D)

XP-D is caused by defective NER, leading to the accumulation of UV-induced DNA damage.

Clinical features include extreme UV sensitivity, early-onset skin cancers (basal cell carcinoma, squamous cell carcinoma, melanoma), and neurological decline (cognitive impairment, sensorineural hearing loss).

Patients have a high predisposition to skin and ocular malignancies due to impaired DNA repair.

Trichothiodystrophy (TTD)

TTD is caused by mutations affecting XPD’s role in transcription rather than NER, leading to defects in gene expression.

Clinical features include brittle hair ("tiger-tail" pattern under polarized light), ichthyosis (scaly skin), developmental delay, short stature, and UV sensitivity.

Unlike XP, TTD is not associated with cancer risk, likely due to its predominant impact on TFIIH-mediated transcription rather than DNA repair.

Cockayne Syndrome (CS)

CS overlaps with XP, but presents with progressive neurodegeneration rather than cancer susceptibility.

Clinical features of CS include severe growth failure, microcephaly, progressive neurodevelopmental impairment, sun sensitivity, and premature aging (progeroid features).

Cerebro-Oculo-Facio-Skeletal Syndrome (COFS)

COFS is a severe congenital disorder linked to homozygous or compound heterozygous ERCC2 mutations (e.g., Gly47Arg variant).

Clinical features include severe microcephaly, cataracts, optic atrophy, joint contractures, deafness, thrombocytopenia, failure to thrive, recurrent pneumonia, and early death.

Due to its profound impact on TFIIH function, COFS results in global transcriptional defects and is often fatal in infancy or early childhood.

ERCC2 and Cancer

Somatic ERCC2 mutations are implicated in cancer development, particularly in bladder cancer (BLCA), where mutations occur in ~10% of cases. These mutations affect the helicase domains of XPD, impairing NER and leading to:

• Increased tumor mutation burden, particularly at CTCF-cohesin binding sites (CBSs) and transcriptionally active regions.
• APOBEC-driven mutagenesis characterized by cytosine-to-thymine (C>T) transitions.
• Altered replication timing and chromatin accessibility, influencing tumor evolution.
• Enhanced sensitivity to cisplatin-based chemotherapy, making ERCC2 a predictive biomarker for treatment selection in bladder cancer patients.

Who Should Get ERCC2 Genetic Testing?

ERCC2 genetic testing is recommended for individuals displaying clinical features suggestive of Xeroderma Pigmentosum group D (XP-D), Cockayne Syndrome (CS), or Trichothiodystrophy (TTD). 

These conditions are associated with extreme photosensitivity, early-onset skin cancers, developmental delays, growth failure, brittle hair and nails, and ichthyosis (scaly skin). 

Identifying a pathogenic ERCC2 mutation in symptomatic individuals can confirm the diagnosis and guide management.

Testing is also valuable for individuals with a family history of XP-D, CS, or TTD. Family members can be tested to determine carrier status or assess the likelihood of having affected children. Prenatal testing is available for families with a known ERCC2 mutation, allowing for early diagnosis before birth. 

Given the complex nature of ERCC2-related disorders, genetic counseling is strongly recommended before and after testing to help individuals and families understand the implications of the results, inheritance patterns, and reproductive risks.

Test Procedure and Interpretation

The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for ERCC2 genetic testing are considered to be without mutations that can alter the activity of the ERCC2 proteins.

Clinical Implications of Positive ERCC2 Mutations

The clinical implications of a positive ERCC2 mutation test result will vary by individual, although ERCC2 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of various symptoms.

Patients or practitioners with questions about the clinical implications of ERCC2 mutations should seek further assessment with a genetic counselor or expert. 

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