ERCC2 – Xeroderma Pigmentosum Group D

ERCC2 encodes the ATP-dependent DNA helicase XPD, a core subunit of the TFIIH transcription/repair complex required for global genome and transcription-coupled nucleotide excision repair (NER). Biallelic loss-of-function variants in ERCC2 cause xeroderma pigmentosum group D, an autosomal recessive disorder marked by extreme ultraviolet (UV) sensitivity and a high risk of early skin neoplasms.

Autosomal recessive inheritance is supported by compound heterozygous mutations segregating in two unrelated families: a Vietnamese pedigree with four affected sibs carrying ERCC2:c.1354C>T (p.Gln452Ter) and ERCC2:c.2048G>A (p.Arg683Gln) ([PMID:32047639]) and a Japanese patient harboring ERCC2:c.1445_1447del (p.Thr482del) and ERCC2:c.1003C>G (p.Arg335Gly) ([PMID:32802388]). In total, five unrelated probands have confirmed biallelic ERCC2 variants with full segregation.

Variant spectrum in XP-D includes nonsense, frameshift and missense alleles clustering in helicase domains critical for ATP binding and DNA unwinding. The most recurrent pathogenic changes—p.Gln452Ter and p.Arg683Gln—result in truncated or functionally impaired XPD, abrogating NER activity. ERCC2:c.1354C>T (p.Gln452Ter) serves as a representative, clinically validated variant.

Functional assays demonstrate that patient fibroblasts fail to recover UV-induced DNA damage, recapitulating NER deficiency in vitro ([PMID:32047639]). Yeast complementation studies of TTD and XP-D mutations confirm loss of XPD-mediated rescue of a rad3 null allele, indicating essential roles in transcription and DNA repair ([PMID:7629061]). Biochemical reconstitution of TFIIH harboring XP-D mutations reveals both impaired helicase activity and reduced basal transcription initiation, correlating with disease phenotype ([PMID:12820975]).

The mechanism of pathogenicity is loss of helicase function leading to defective NER and accumulation of UV lesions, resulting in early‐onset cutaneous malignancies. Experimental data across cellular, yeast and biochemical models are concordant, supporting a direct genotype-to-phenotype link.

Key take-home: Biallelic ERCC2 variants unequivocally disrupt NER and cause autosomal recessive xeroderma pigmentosum group D, justifying ERCC2 sequencing for early diagnosis and guiding surveillance for UV-induced skin cancers.

References

• Human genome variation • 2020 • A novel nonsense mutation of ERCC2 in a Vietnamese family with xeroderma pigmentosum syndrome group D. PMID:32047639
• Human genome variation • 2020 • A Japanese girl with mild xeroderma pigmentosum group D neurological disease diagnosed using whole-exome sequencing. PMID:32802388
• The Journal of Biological Chemistry • 1995 • Lethality in yeast of trichothiodystrophy (TTD) mutations in the human xeroderma pigmentosum group D gene. Implications for transcriptional defect in TTD. PMID:7629061
• Molecular Cell • 2003 • Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients. PMID:12820975

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