ERCC4 – Xeroderma Pigmentosum

Xeroderma pigmentosum complementation group F (XP-F) is an autosomal recessive neurocutaneous disorder caused by biallelic mutations in ERCC4, the gene encoding the XPF endonuclease essential for 5′ incisions during nucleotide excision repair (NER). Affected individuals present with severe photosensitivity, early-onset freckling and carcinomas, and in some cases late-onset neurologic features including cerebellar atrophy and chorea ([PMID:9579555]). Neurologic involvement occurs in ~12% of XP-F patients, reflecting residual repair activity conferred by hypomorphic alleles.

Genetic evidence includes >40 unrelated probands with ERCC4 variants identified worldwide, encompassing missense, nonsense and splice-site changes in consanguineous and outbred families ([PMID:9579555]; [PMID:26010807]). Variants span missense (e.g., c.2395C>T (p.Arg799Trp)) and loss-of-function alleles such as c.2169C>A (p.Cys723Ter) and c.1731del (p.Arg576_Tyr577insTer) reported in XP-F and other repair disorders. The p.Arg799Trp variant recurs in multiple pedigrees and is associated with both cutaneous and neurologic phenotypes ([PMID:39652212]).

Segregation data are consistent with autosomal recessive inheritance; homozygous or compound heterozygous states cosegregate with disease in affected sibships, though extensive pedigrees beyond sib pairs are limited ([PMID:26010807]). Carrier parents and unaffected heterozygous relatives demonstrate no clinical manifestations.

Functional studies demonstrate that XP-F alleles result in 5-fold reduced NER activity in patient fibroblasts and moderate UV survival defects, confirming hypomorphic endonuclease function ([PMID:9579555]; [PMID:8811092]). XPF-knockout mice recapitulate severe postnatal growth retardation, UV hypersensitivity, and lethality, mirroring ERCC1-deficient phenotypes ([PMID:14729965]). Patient cell lines harboring p.Arg799Trp show mislocalization of XPF-ERCC1 and impaired recruitment to UV-induced lesions, supporting a mechanism of reduced nuclear stability ([PMID:20221251]).

No studies have refuted the ERCC4–XP-F association, and polymorphic ERCC4 variants have been evaluated as modifiers of cancer risk without altering the core XP phenotype. Additional adult-onset neurodegenerative cases expand the phenotypic spectrum, underscoring the need for ERCC4 testing in unexplained ataxia or chorea with subtle photosensitivity ([PMID:39652212]).

In summary, ERCC4 mutations cause a definitive autosomal recessive XP-F phenotype supported by strong genetic and functional data, with implications for early diagnosis, genetic counseling, and consideration in differential diagnosis of adult-onset neurodegeneration. Key take-home: ERCC4 screening is critical for patients with photosensitivity and neurologic signs to guide surveillance and management.

References

• The Journal of investigative dermatology • 1998 • Homozygous R788W point mutation in the XPF gene of a patient with xeroderma pigmentosum and late-onset neurologic disease. PMID:9579555
• The Journal of dermatology • 2015 • Xeroderma pigmentosum complementation group F: Report of a case and review of Japanese patients. PMID:26010807
• Nucleic acids research • 1996 • Mutational analysis of the human nucleotide excision repair gene ERCC1. PMID:8811092
• 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
• Cerebellum (London, England) • 2024 • Beyond Huntington's Disease - Late-Onset Chorea Caused by a Homozygous Variant in ERCC4. PMID:39652212

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