ERCC4 – Xeroderma pigmentosum-Cockayne syndrome complex

Xeroderma pigmentosum-Cockayne syndrome complex (XP-CS) is an autosomal recessive multisystem degenerative disorder characterized by features of both xeroderma pigmentosum and Cockayne syndrome, notably early-onset photosensitivity, neurodevelopmental delay, and skin neoplasms. A comprehensive literature review identified 43 XP-CS patients, 42 of whom had molecular or biochemical confirmation; complementation grouping revealed four XP-CS subgroups, with 3 patients assigned to the XP-F complementation group corresponding to biallelic ERCC4 mutations ([PMID:28376890]).

Genetic evidence for ERCC4 involvement in XP-CS is limited: only 3 unrelated probands carrying biallelic ERCC4 defects have been reported, with no formal segregation studies published ([PMID:28376890]). A truncating mutation, c.2169C>A (p.Cys723Ter), has been documented in XP-F patients and shown to abolish the XPF endonuclease C-terminal function ([PMID:24412486]). Functional studies provide moderate evidence: XPF-deficient mice exhibit postnatal growth retardation, UV hypersensitivity, and early lethality mirroring human XP-F phenotypes, and reintroduction of wild-type ERCC4 restores nucleotide excision repair in cellular assays ([PMID:14729965]). The pathogenic mechanism is consistent with loss-of-function due to failure of 5′ incision during nucleotide excision repair, leading to DNA damage accumulation.

While genetic data remain limited by small patient numbers, convergent functional studies in animal and cellular models support the role of ERCC4 loss-of-function in XP-CS. Key take-home: ERCC4 should be included in diagnostic gene panels for XP-CS patients presenting with combined photosensitivity and neurodegeneration, and functional assays of XPF activity can aid variant interpretation.

References

• Orphanet journal of rare diseases • 2017 • Xeroderma pigmentosum-Cockayne syndrome complex. PMID:28376890
• 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
• Gene • 2014 • A nonsense mutation in the Xeroderma pigmentosum complementation group F (XPF) gene is associated with gastric carcinogenesis. PMID:24412486

Evidence Based Scoring (AI generated)