ERCC4 – Xeroderma pigmentosum group F

ERCC4 encodes the XPF structure-specific endonuclease that acts in a complex with ERCC1 to initiate 5′-incision during nucleotide excision repair. Pathogenic variants in ERCC4 cause xeroderma pigmentosum complementation group F (xeroderma pigmentosum group F), an autosomal recessive disorder characterized by extreme sun sensitivity and increased risk of cutaneous malignancies.

A Japanese series reported 23 unrelated XP-F probands with biallelic ERCC4 mutations, defining the clinical spectrum and confirming autosomal recessive inheritance (PMID:26010807). Segregation analysis in a consanguineous pedigree revealed two additional affected relatives (mother and sister with photosensitivity), reinforcing co-segregation of ERCC4 variants with disease (PMID:26010807).

Variant spectrum includes missense and truncating alleles across the nuclease domain. Notably, c.2395C>T (p.Arg799Trp) is recurrent in compound heterozygotes presenting photosensitivity and pigmentary changes, supporting pathogenicity of this allele (PMID:36816046). Other reported alleles include c.1349G>A (p.Trp450Ter) in trans configuration in adult-onset cases with mixed neurological and dermatological features.

Functional assays demonstrate reduced UV-C survival and intermediate repair capacity in patient fibroblasts, with restoration of normal incision activity upon wild-type ERCC4 transfection (PMID:26010807). XPF-deficient mice show UV hypersensitivity and early death consistent with human XP phenotypes (PMID:14729965), and mislocalization of XPF-ERCC1 abolishes nuclear repair in cell models (PMID:20221251).

In summary, autosomal recessive ERCC4 variants cause xeroderma pigmentosum group F with strong genetic and functional concordance. The combination of multiple unrelated probands, segregation data, and robust experimental rescue studies supports a Strong gene–disease association. Key Take-home: ERCC4 sequencing enables definitive diagnosis of XP-F and guides sun‐protective surveillance to mitigate skin cancer risk.

References

• The Journal of dermatology • 2015 • Xeroderma pigmentosum complementation group F: Report of a case and review of Japanese patients. PMID:26010807
• Molecular and cellular biology • 2004 • Growth retardation, early death, and DNA repair defects in mice deficient for the nucleotide excision repair enzyme XPF. PMID:14729965
• PLoS genetics • 2010 • Mislocalization of XPF-ERCC1 nuclease contributes to reduced DNA repair in XP-F patients. PMID:20221251
• Frontiers in genetics • 2023 • Case report: Variants in the ERCC4 gene as a rare cause of cerebellar ataxia with chorea. PMID:36816046

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