XPC – Xeroderma Pigmentosum group C

Xeroderma Pigmentosum complementation group C (XP-C) is an autosomal recessive disorder caused by biallelic pathogenic variants in XPC, a key DNA damage sensor in global genome nucleotide excision repair (Gene Symbol). Affected individuals present with early-onset cutaneous photosensitivity (HP:0000992), freckling, and dramatically increased risk of ultraviolet-induced skin cancers; some develop neurologic or neurobehavioral features such as mutism (HP:0002300) and hyperactivity (HP:0000752) ([PMID:9804340]).

Inheritance is autosomal recessive. Segregation analyses across multiple consanguineous and multiplex families demonstrate segregation of XPC variants with disease, including seven affected siblings in one familial melanoma pedigree ([PMID:38364385]). Case series have identified over 100 unrelated XP-C probands harboring truncating, splice, missense, and deep-intronic variants.

The variant spectrum includes loss-of-function mutations such as the founder c.1643_1644del (p.Val548AlafsTer25) in North African and Maghreb populations (present in 56 of 64 XP-C probands; founder effect) ([PMID:20054342]). Additional pathogenic alleles include c.2033+2T>C (p.?) and missense changes affecting conserved domains. Recurrent and private variants together confirm allelic heterogeneity.

Functional assays in patient fibroblasts and animal models substantiate pathogenicity. XP-C cells exhibit markedly reduced unscheduled DNA synthesis, defective plasmid reactivation, and sensitivity to UVB; Xpc−/− mice show increased spontaneous and UVB-induced skin tumorigenesis with characteristic Trp53 C→T mutation signatures ([PMID:10749125]). In vitro studies reveal that XPC stability is regulated by RAD23B and that damage-induced XPC stabilization promotes repair ([PMID:12815074]).

Some polymorphism studies in melanoma and colorectal cancer cohorts find no association between common XPC variants (e.g., p.Arg492His, p.Val499Ala) and sporadic cancer risk, underscoring the difference between rare pathogenic alleles and low‐penetrance SNPs ([PMID:15494739]).

In summary, definitive evidence establishes XPC as the disease gene for XP-C through robust genetic segregation, clear functional defects in NER, and animal phenotypes that mirror human pathology. Molecular diagnosis of XPC variants enables prompt photoprotection, genetic counseling, and surveillance for skin cancers. Key Take-home: Biallelic loss-of-function XPC variants cause XP-C, and early genetic diagnosis guides prevention of UV-induced malignancies.

References

• The Journal of investigative dermatology • 1998 • Xeroderma pigmentosum group C splice mutation associated with autism and hypoglycinemia. PMID:9804340
• The Journal of investigative dermatology • 2010 • A prevalent mutation with founder effect in xeroderma pigmentosum group C from north Africa. PMID:20054342
• Cancer research • 2000 • Genotype-specific Trp53 mutational analysis in ultraviolet B radiation-induced skin cancers in Xpc and Xpc Trp53 mutant mice. PMID:10749125
• 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
• European Journal of Human Genetics • 2005 • No association between three xeroderma pigmentosum group C and one group G gene polymorphisms and risk of cutaneous melanoma. PMID:15494739

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