ERCC3 – Xeroderma pigmentosum-Cockayne syndrome complex

Xeroderma pigmentosum-Cockayne syndrome complex is a rare autosomal recessive neurocutaneous disorder characterized by early-onset photosensitivity, progressive neurodegeneration, and a high skin cancer risk in survivors. Patients are classified into four complementation groups (XP‐B, ‐D, ‐F, ‐G) based on the mutated nucleotide excision repair (NER) gene. The XP‐B group is caused by biallelic pathogenic variants in ERCC3 and accounts for approximately 12% (5/42) of molecularly confirmed XP-CS cases (PMID:28376890).

Genetic analyses in multiple cohorts identified a total of eight unrelated XP-B probands—five in a multi‐patient survey and three in a family segregating two affected siblings and one isolated case (PMID:28376890, PMID:8304337). All patients exhibited an autosomal recessive inheritance pattern with two affected siblings segregating ERCC3 variants. Reported variant types in XP-B include missense, splice‐site, and frameshift changes.

The variant spectrum in XP-B comprises missense substitutions in conserved helicase domains (e.g., c.296T>C (p.Phe99Ser)) and splice‐site or frameshift alterations leading to truncated XPB protein. The recurrent missense allele c.296T>C (p.Phe99Ser) was identified in three XP-CS patients and is associated with complete loss of NER function in patient cells (PMID:8304337).

Functional assays in vitro and in vivo demonstrate that XPB—encoded by ERCC3—is a DNA‐dependent ATPase/helicase subunit of the TFIIH complex, essential for both NER and basal transcription. Microinjection and cell‐free extracts confirm that ERCC3 variants abrogate NER excision repair activity and impair transcription initiation (PMID:8157004). A naturally occurring frameshift mutation (c.2218-6C>A) in patient XP11BE reduces XPB helicase and ATPase activities, leading to severe NER deficiency and diminished transcriptional competence (PMID:8663148).

These concordant genetic and functional data support a loss‐of‐function mechanism for ERCC3 in XP-CS. ERCC3‐deficient cells display profound UV sensitivity, failure of transcription‐coupled repair, and disrupted chromatin maintenance, mirroring the clinical phenotype of skin tumor development and neurodegeneration.

In summary, autosomal recessive ERCC3 variants in XP‐B patients underlie the XP-CS complex through combined defects in DNA repair and transcription. Molecular diagnosis of ERCC3 mutations is critical for accurate prognosis, genetic counseling, and may guide future therapeutic strategies targeting NER or transcription pathways.

Key Take-home: Biallelic ERCC3 loss‐of‐function variants cause XP-CS by abolishing TFIIH‐mediated NER and transcription, underpinning the neurocutaneous phenotype and informing clinical management.

References

• Orphanet Journal of Rare Diseases • 2017 • Xeroderma pigmentosum-Cockayne syndrome complex PMID:28376890
• 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 EMBO Journal • 1994 • Correction of xeroderma pigmentosum repair defect by basal transcription factor BTF2 (TFIIH) PMID:8157004
• 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

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