XPC – Xeroderma pigmentosum group C

Xeroderma pigmentosum group C is an autosomal recessive disorder characterized by extreme photosensitivity and a marked predisposition to early-onset skin cancers. Biallelic loss-of-function variants in the XPC gene underlie defective global genome nucleotide excision repair, leading to impaired removal of UV-induced DNA lesions and genomic instability.

Genetic studies have identified at least eight unrelated probands harboring pathogenic XPC alleles, including the recurrent nonsense variant c.1735C>T (p.Arg579Ter) homozygous in a Korean patient with a milder phenotype (PMID:37109656). Splice-site and intronic branchpoint mutations such as c.413-24A>G disrupt normal pre-mRNA splicing and reduce XPC transcript levels to <5% of normal (PMID:14662655). Two consanguineous families demonstrated segregation of intron 3 branchpoint and initiation codon variants with disease in five affected siblings, confirming autosomal recessive inheritance.

Functional evidence from Xpc−/− mice reveals a profound nucleotide excision repair defect and high susceptibility to UV-B–induced skin carcinogenesis in both homozygous and heterozygous states (PMID:11376686). In vitro, RAD23B and centrin-2 stabilize XPC and facilitate DNA damage recognition, whereas branchpoint and missense mutations abrogate these interactions and lead to proteasomal degradation of XPC (PMID:12815074; PMID:17154534). Rescue assays confirm that even low-level restoration of XPC expression can partially recover nucleotide excision repair activity.

One reported case exhibited a milder clinical course despite carrying the rs121965088 (c.1735C>T, p.Arg579Ter) variant, suggesting the influence of genetic modifiers or hypomorphic alleles (PMID:37109656). No studies to date have refuted the causative role of XPC in XP-C, and all conflicting observations point to phenotype variability rather than gene–disease dissociation.

Overall, genetic and experimental data consistently support a Strong clinical validity for the XPC–xeroderma pigmentosum group C association. The integration of detailed genotype–phenotype correlations, segregation in multiple families, and concordant mechanistic studies in cellular and animal models underscores the robust nature of this gene–disease relationship.

Key Take-home: Early genetic testing for XPC variants enables precise diagnosis of XP-C, guiding photoprotection measures and surveillance for skin malignancies.

References

• Medicina (Kaunas, Lithuania) • 2023 • Whole Exome Sequencing of a Patient with a Milder Phenotype of Xeroderma Pigmentosum Group C. PMID:37109656
• Human molecular genetics • 2004 • Two essential splice lariat branchpoint sequences in one intron in a xeroderma pigmentosum DNA repair gene: mutations result in reduced XPC mRNA levels that correlate with cancer risk. PMID:14662655
• Mutation research • 2001 • Cancer predisposition in mutant mice defective in multiple genetic pathways: uncovering important genetic interactions. PMID:11376686
• Genes & development • 2003 • A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein. PMID:12815074
• Biochemistry • 2006 • Biochemical and structural domain analysis of xeroderma pigmentosum complementation group C protein. PMID:17154534

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