ERCC3 – Xeroderma Pigmentosum

ERCC3 encodes the XPB helicase subunit of the transcription/repair factor TFIIH, which is essential for both nucleotide excision repair (NER) and transcription initiation. Biallelic pathogenic variants in ERCC3 define xeroderma pigmentosum complementation group B (XP-B), an autosomal recessive disorder characterized by photosensitivity, early-onset cutaneous malignancies, and in some cases combined XP/Cockayne syndrome features when transcription is also compromised. The combined deficiency in NER and basal transcription underlies the severity and heterogeneity of the clinical presentation (PMID:8663148).

Genetic evidence includes at least seven unrelated XP-B probands from five families harboring compound heterozygous or homozygous ERCC3 variants: the recurrent intronic splice acceptor mutation c.2218-6C>A in multiple XP/CS complex families and the missense variant c.296T>C (p.Phe99Ser) in XP only patients (PMID:8304337; PMID:16947863). All show autosomal recessive inheritance with segregation in sibships. No ERCC3-transcript expression from the mutant allele confirms loss of function in patient cells.

The variant spectrum for XP-B includes frameshift, nonsense, splice, and missense mutations affecting the conserved helicase domains and C-terminal region of XPB. For example, the intronic splice variant c.2218-6C>A disrupts normal C-terminal structure and impairs interaction with the XPF-ERCC1 endonuclease, whereas c.296T>C (p.Phe99Ser) abolishes ATPase activity of the helicase (PMID:8663148; PMID:8304337).

Functional assays demonstrate that XP-B mutations lead to a 70–90% reduction in 3′→5′ helicase and DNA-dependent ATPase activities, defective open-complex formation during NER, and decreased basal transcriptional output in vitro. Dominant-negative expression of helicase-dead XPB variants in cell-free repair assays and microinjection rescue studies confirm a dual mechanism of pathogenesis—haploinsufficiency for transcription and complete loss of NER function (PMID:8157004).

No studies have refuted the causal relationship between ERCC3 and XP-B. The phenotypic overlap with Cockayne syndrome in XP/CS complex families highlights allele-specific effects on transcription without confounding evidence disputing core NER defects.

In summary, ERCC3 meets ClinGen criteria for a Strong gene–disease association based on biallelic variants in multiple unrelated probands, family segregation, and concordant functional data. Genetic evidence is Strong (seven probands, five families; AR inheritance; segregation) and functional evidence is Strong (multiple in vitro and in vivo assays demonstrate mechanistic concordance). ERCC3 variant screening enables definitive diagnosis, informs prognosis for skin cancer risk, and supports targeted management including rigorous photoprotection and surveillance.

Key take-home: Biallelic ERCC3 variants cause xeroderma pigmentosum group B through combined NER deficiency and transcriptional impairment, making genetic testing essential for early diagnosis and tailored patient care.

References

• American journal of human genetics • 1994 • Clinical heterogeneity within xeroderma pigmentosum associated with mutations in the DNA repair and transcription gene ERCC3. PMID:8304337
• The Journal of biological chemistry • 1996 • A 3' --> 5' XPB helicase defect in repair/transcription factor TFIIH of xeroderma pigmentosum group B affects both DNA repair and transcription. PMID:8663148
• Human mutation • 2006 • Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome. PMID:16947863
• The EMBO journal • 1994 • Correction of xeroderma pigmentosum repair defect by basal transcription factor BTF2 (TFIIH). PMID:8157004

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