ERCC4 – XFE Progeroid Syndrome

XFE Progeroid Syndrome is an autosomal recessive segmental progeroid disorder characterized by accelerated aging, photosensitivity, neurodegeneration, and cutaneous atrophy. Affected individuals often present in adulthood with progressive cerebellar ataxia, chorea, dysarthria, bilateral sensorineural hearing loss, and extensive pigmented skin lesions. Pathogenic variants in ERCC4, encoding the XPF endonuclease subunit of the ERCC1–XPF complex, underlie defects in nucleotide excision repair (NER) and interstrand crosslink (ICL) repair.

Genetic Evidence

Biallelic ERCC4 variants have been reported in two unrelated cases of segmental progeroid syndrome ([PMID:29105242]) and one adult-onset case with cerebellar ataxia, chorea, dysarthria, UV hypersensitivity, and skin lesions ([PMID:36816046]). In the first cohort study, one patient was compound heterozygous for c.2395C>T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130AspfsTer18), and a second patient carried two variants in cis (c.1488A>T; c.2579C>A) with accelerated aging features but incomplete functional characterization ([PMID:29105242]). A 53-year-old patient harbored c.2395C>T (p.Arg799Trp) and c.1349G>A (p.Trp450Ter) in trans, correlating with adult‐onset neurological decline and progeroid skin findings ([PMID:36816046]). Segregation data support autosomal recessive inheritance without additional affected relatives reported.

Functional Evidence

ERCC4 encodes the XPF nuclease that heterodimerizes with ERCC1 to incise damaged DNA 5′ to lesions in NER and ICL repair. The p.Arg799Trp substitution retains catalytic activity but mislocalizes XPF–ERCC1 to the cytoplasm, reducing nuclear DNA repair capacity in patient cells ([PMID:20221251]). In a mouse Xpf knockout model, loss of XPF–ERCC1 function causes growth retardation, accelerated aging phenotypes, UV hypersensitivity, and early lethality, recapitulating key aspects of human XFE progeroid syndrome ([PMID:22353549]).

Conflicting Evidence

No studies to date have refuted the association between biallelic ERCC4 variants and XFE progeroid syndrome; variant pathogenicity has been consistent across assays.

Conclusion

Collectively, three unrelated probands with biallelic ERCC4 variants and concordant functional data support a limited but compelling association with XFE progeroid syndrome. Further identification of affected families and segregation analyses will be necessary to strengthen clinical validity. Key take-home: ERCC4 pathogenic variants should be considered in adults presenting with progressive neurodegeneration, UV sensitivity, and accelerated aging features to guide genetic diagnosis and management.

References

• Human Mutation • 2018 • ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes PMID:29105242
• Frontiers in Genetics • 2023 • Case report: Variants in the ERCC4 gene as a rare cause of cerebellar ataxia with chorea PMID:36816046
• PLoS Genetics • 2010 • Mislocalization of XPF-ERCC1 nuclease contributes to reduced DNA repair in XP-F patients PMID:20221251
• Genes to Cells • 2012 • Xeroderma pigmentosum group F protein binds to Eg5 and is required for proper mitosis: implications for XP-F and XFE PMID:22353549

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