ERCC3

The ERCC3 gene, also known as XPB, encodes a DNA-dependent ATPase/helicase that plays a critical role in both nucleotide excision repair (NER) and transcription regulation as part of the transcription factor IIH (TFIIH) complex. 

Mutations in ERCC3 can impair DNA repair and gene expression, leading to severe genetic disorders such as Xeroderma Pigmentosum Group B (XP-B), Trichothiodystrophy Type 2 (TTD2), and Cockayne Syndrome (CS), as well as increasing susceptibility to breast and other cancers.

What is ERCC3 (Excision Repair Cross-Complementation Group 3)

The ERCC3 gene (Excision Repair Cross-Complementation Group 3), also known as XPB, is located on chromosome 2q14.3 and encodes a DNA-dependent ATPase/helicase. It is a critical component of transcription factor IIH (TFIIH), a multi-protein complex involved in both nucleotide excision repair (NER) and basal transcription regulation. 

In DNA repair, ERCC3 unwinds damaged DNA to facilitate the removal of bulky lesions caused by UV radiation and chemical mutagens. It also plays an essential role in transcription by interacting with RNA polymerase II, ensuring proper gene expression. 

Additionally, ERCC3 is involved in cellular stress responses and genomic stability, helping prevent DNA damage accumulation that could lead to disease.

Genetic Mutations and Associated Disorders

Mutations in ERCC3 disrupt its ability to repair DNA and regulate transcription, leading to severe genetic disorders. ERCC3 mutations, particularly in breast cancer, compromise genomic stability and increase cancer risk by impairing DNA repair mechanisms.

Xeroderma Pigmentosum Group B (XP-B)

One such condition is Xeroderma Pigmentosum Group B (XP-B), an autosomal recessive disorder characterized by extreme UV sensitivity and a high risk of early-onset skin cancer. 

This results from defects in the nucleotide excision repair pathway, which normally removes UV-induced DNA damage. 

XP-B is characterized by extreme UV sensitivity, increased risk of skin cancers, freckle-like pigmentation, and ocular abnormalities, with some cases presenting progressive neurological deterioration, sensorineural hearing loss, and cognitive impairment. 

Severe cases overlapping with Cockayne Syndrome (XPB/CS) exhibit growth failure, microcephaly, demyelination, premature aging features, and profound neurodevelopmental impairments.

Trichothiodystrophy Type 2 (TTD2)

Another disorder linked to ERCC3 mutations is Trichothiodystrophy Type 2 (TTD2), a neurodevelopmental disorder featuring brittle hair, intellectual disability, and growth failure. 

TTD2 is marked by brittle, sulfur-deficient hair, photosensitivity, congenital ichthyosis, short stature, mild to moderate developmental delays, and recurrent infections, but without an increased risk of cancer. Some individuals present with mild intellectual disability and immune dysfunction, while neurological involvement is typically absent or minimal.

Cockayne Syndrome (CS)

Cockayne Syndrome (CS) is a rare autosomal recessive disorder characterized by progressive neurodevelopmental decline, growth failure, microcephaly, premature aging (progeroid features), and severe photosensitivity. 

Affected individuals often experience sensorineural hearing loss, cataracts, cachexia, joint contractures, and progressive demyelination leading to severe neurological impairment. 

Unlike Xeroderma Pigmentosum, CS does not significantly increase the risk of skin cancer despite UV sensitivity.

Breast Cancer Susceptibility

Recent research has identified ERCC3 as a breast cancer susceptibility gene, particularly in early-onset cases. A novel nonsense mutation, p.Y116X, was found in a Han-Chinese family with hereditary breast cancer. 

Bioinformatic analysis indicates that ERCC3 expression is negatively associated with hormone receptor-positive breast cancers, suggesting that ERCC3 loss may contribute to more aggressive, hormone receptor-negative disease. 

The functional consequences of ERCC3 mutations in breast cancer are still under investigation, but current evidence suggests a role in tumor progression and genomic instability.

Cancer Implications

Beyond breast cancer, ERCC3 mutations and copy number variations (CNVs) have been implicated in various cancers, including ovarian, lung, bladder, colorectal, and thyroid cancer. 

Loss-of-function mutations in ERCC3 impair DNA repair, increasing genomic instability and the likelihood of tumor development.

Studies using c-BioPortal data have also shown that ERCC3 amplifications are enriched in breast invasive carcinoma, while deep deletions are more common in metaplastic breast cancer, further supporting its role in cancer biology.

ERCC3 is a potential target in cancer treatment due to its role in DNA repair. 

Who Should Get ERCC3 Genetic Testing?

The following groups should consider ERCC3 genetic testing: 

Genetic testing for ERCC3 is crucial for individuals presenting with clinical features suggestive of Xeroderma Pigmentosum group B (XP-B), Cockayne Syndrome (CS) (particularly severe forms), or combined XP/CS. Patients with ERCC3-related disorders often exhibit:

• Extreme sensitivity to sunlight (photosensitivity)
• Early-onset skin cancers (including basal cell carcinoma and squamous cell carcinoma)
• Severe neurological issues, including progressive neurodegeneration
• Developmental delay or intellectual disability
• Growth failure and cachexia

Specific groups of people who may consider ERCC3 genetic testing may include: 

Individuals with a Family History of XP-B, CS, or Combined XP/CS

Genetic testing can help determine carrier status of at-risk family members and assess the likelihood of having an affected child. Since ERCC3-related conditions are inherited in an autosomal recessive manner, both parents must carry a pathogenic mutation for a child to be affected.

Prenatal Testing

For families with a known ERCC3 mutation, prenatal testing can provide early diagnosis during pregnancy. This may be useful for families considering reproductive options.

Genetic Counseling

Given the complex inheritance patterns and potential clinical variability, genetic counseling is strongly recommended both before and after testing. Counselors can help patients and families understand the results, discuss reproductive risks, and explore next steps for management.

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 ERCC3 genetic testing are considered to be without mutations that can alter the activity of the ERCC3 proteins.

Clinical Implications of Positive ERCC3 Mutations

The clinical implications of a positive ERCC3 mutation test result will vary by individual, although ERCC3 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 ERCC3 mutations should seek further assessment with a genetic counselor or expert. 

Clinical Implications of Negative ERCC3 Mutations

A negative result does not rule out other genetic causes of photosensitivity, neurological dysfunction, or developmental abnormalities.

If clinical suspicion remains high, consider testing other DNA repair genes (e.g., ERCC2, ERCC6, ERCC8, XPA, XPC).

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