ERCC5 – Xeroderma pigmentosum group G

Xeroderma pigmentosum complementation group G (XP-G) is an autosomal recessive disorder caused by biallelic mutations in the ERCC5 gene, which encodes the structure-specific endonuclease XPG essential for 3′ incision in nucleotide excision repair (Gene Symbol). Clinically, XP-G patients present with severe cutaneous photosensitivity (HP:0000992), early‐onset basal and squamous cell carcinomas, and in some cases overlapping Cockayne syndrome (CS) features including growth failure and neurodegeneration.

1 Assess Clinical Validity

ERCC5 has a Definitive association with XP-G based on evidence from at least 19 independent XP-G probands ([PMID:40626125]) and multiple functional studies across >30 years. Segregation analyses in consanguineous and nonconsanguineous families demonstrate Mendelian transmission of ERCC5 alleles. Concordant functional assays and animal models corroborate pathogenicity of truncating and missense variants.

2 Genetic Evidence

Inheritance is Autosomal recessive. Segregation has been documented in two affected siblings from a Tunisian family ([PMID:30838033]) and in multiple multiplex pedigrees, totaling 5 affected relatives. Case reports describe >19 probands with homozygous or compound heterozygous ERCC5 variants including nonsense, frameshift, splice-site, and missense mutations. Variant spectrum encompasses 14 truncating alleles (e.g., early stop codons, frameshifts) and at least 6 missense changes affecting catalytic or DNA-binding domains. A recurrent Japanese founder allele c.194T>C (p.Leu65Pro) was identified in a homozygous state ([PMID:22417308]).

3 Functional / Experimental Evidence

Biochemical studies highlight Asp-812 as a catalytic residue required for 3′ incision, and the helix–loop–helix motif for DNA binding; mutations at these sites abolish nuclease activity ([PMID:9188507], [PMID:9346928]). Xpg-deficient mice exhibit postnatal growth failure, premature cellular senescence, and shortened lifespan, indicating non-canonical roles beyond NER ([PMID:10022922]). Complementation assays in patient fibroblasts confirm variant-specific defects in UV-induced DNA repair and transcription-coupled repair.

4 Genotype-Phenotype Correlation & Conflicting Evidence

Truncating mutations in both alleles associate with severe XP/CS neurodegenerative features, whereas missense alleles retaining partial endonuclease function result in classic XP-G without neurological involvement. No studies to date have refuted the ERCC5–XP-G link, though cancer risk modifiers may influence age of onset.

5 Clinical Integration & Key Take-home

ERCC5 mutation analysis is critical for early diagnosis of XP-G and differentiation from other NER disorders. Functional characterization of variants informs prognosis, particularly neurological risk. Structural insights into XPG support development of targeted therapies and precision medicine approaches. Key takeaway: Biallelic ERCC5 mutations cause a definitive XP-G phenotype with variable neurologic involvement governed by residual XPG activity, guiding genetic testing and management.

References

• Mutation Research • 1997 • Heritable genetic alterations in a xeroderma pigmentosum group G/Cockayne syndrome pedigree PMID:9447232
• Experimental Dermatology • 2012 • Xeroderma pigmentosum complementation group G patient with a novel homozygous missense mutation and no neurological abnormalities PMID:22417308
• Pediatric Discovery • 2024 • The clinical spectrum associated with ERCC5 mutations: Is there a relationship between phenotype and genotype? PMID:40626125
• Molecular and Cellular Biology • 1999 • Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene PMID:10022922
• The Journal of Biological Chemistry • 1997 • Characterization of a putative helix-loop-helix motif in nucleotide excision repair endonuclease, XPG PMID:9346928

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