ERCC2 – Xeroderma pigmentosum

ERCC2 (XPD) is essential for nucleotide excision repair (NER) and basal transcription as part of the TFIIH complex. Biallelic ERCC2 variants underlie the autosomal recessive xeroderma pigmentosum complementation group D (XP-D), characterized by sun sensitivity, basal cell carcinomas, and progressive neurological degeneration. Numerous unrelated patients (>10 probands) have been reported with compound heterozygous or homozygous ERCC2 mutations, with confirmed parental segregation and concordant functional deficits in NER and TFIIH activity, supporting a Definitive gene–disease relationship ([PMID:18637129]; [PMID:7585650]; [PMID:18470933]).

Genetic evidence includes compound heterozygosity for common and null alleles—most frequently c.2047C>T (p.Arg683Trp)—in multiple XP-D patients, with segregation of variants in parental studies and absence of additional ERCC2 variants in controls. Case reports describe a 16-year-old boy with XP2GO harboring c.2047C>T and a novel c.2009delG (p.Gly670AlafsTer39) variant, confirming biallelic inheritance and meeting ClinGen genetic cap thresholds (Strong genetic evidence). No other genes were implicated in these families, and carrier parents were asymptomatic.

Functional studies demonstrate impaired NER capacity in patient fibroblasts (reduced post-UV survival D₃₇ ≈3.8 J/m² [PMID:18637129]), defective removal of cyclobutane pyrimidine dimers and 6-4 photoproducts, aberrant TFIIH recruitment, and loss of XPD helicase activity in recombinant assays. TFIIH complexes with XP-D mutations show reduced transcriptional transactivation by nuclear receptors and delayed repair protein dissociation at DNA damage sites, consistent with the XP-D phenotype (Moderate functional evidence).

No studies have robustly refuted the ERCC2–XP association or assigned an alternative molecular etiology. The breadth of genotype–phenotype data and reproducible functional impairments across assays confirm that ERCC2 deficiency causes XP-D. Early molecular diagnosis enables strict UV protection, reducing cutaneous malignancies while neurological degeneration may progress despite treatment.

Key Take-home: Autosomal recessive ERCC2 mutations cause XP-D; genetic confirmation guides sun-protection strategies, cancer surveillance, and family counseling.

References

• Experimental dermatology • 2009 • Strict sun protection results in minimal skin changes in a patient with xeroderma pigmentosum and a novel c.2009delG mutation in XPD (ERCC2). PMID:18637129
• Cancer research • 1995 • Defects in the DNA repair and transcription gene ERCC2 in the cancer-prone disorder xeroderma pigmentosum group D. PMID:7585650
• Human mutation • 2008 • Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy. PMID:18470933

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