XPA – Xeroderma Pigmentosum Group A

Xeroderma pigmentosum group A (XP-A) is an autosomal recessive disorder caused by biallelic loss-of-function variants in XPA. Clinically, XP-A patients exhibit severe photosensitivity, early-onset freckling, basal cell carcinoma, and progressive neurological abnormalities due to impaired global genome and transcription-coupled nucleotide excision repair.

Inheritance is autosomal recessive, with over 100 affected individuals reported worldwide and segregation in multiple sibships ([PMID:1372102]). The mutation spectrum includes nonsense (e.g., p.Tyr116Ter, p.Arg207Ter, p.Arg211Ter), splice-site (IVS3-1G>C founder allele), frameshift, and missense variants. The IVS3-1G>C splice acceptor site mutation is prevalent in Japanese XP-A patients and accounts for a large founder effect ([PMID:7577588]). Compound heterozygosity and homozygosity for these pathogenic alleles consistently co-segregate with disease in multiple families.

Segregation analysis in sib pairs and extended pedigrees confirms the AR inheritance, with at least 4 additional affected relatives documented in published kindreds ([PMID:7962783]).

Functional studies demonstrate that XPA deficiency abolishes DNA damage recognition and excision repair. Xpa-null mice show complete NER deficiency, elevated UV-induced skin carcinogenesis, and immunosuppression mirroring human XP-A ([PMID:11376684]). In vitro assays of truncated and missense XPA proteins reveal loss of DNA binding and failure to complement repair in cell-free systems.

The recurrent nonsense variant c.631C>T (p.Arg211Ter) leads to premature truncation, absent XPA protein, and near-zero repair activity in patient fibroblasts and prenatal diagnoses ([PMID:15214909]). Hypomorphic splice mutants with trace protein retain residual repair capacity correlating with milder phenotypes.

No studies have refuted the XPA–XP-A association. The weight of genetic segregation, recurrent founder alleles, and concordant functional/animal model data establishes a Definitive gene–disease relationship.

Key take-home: Biallelic loss-of-function XPA variants cause classic XP-A; early molecular diagnosis enables UV protection strategies to delay skin cancer and mitigate neurological decline.

References

• Mutation Research • 1992 • Three nonsense mutations responsible for group A xeroderma pigmentosum PMID:1372102
• The British Journal of Dermatology • 1995 • Correlation of the clinical manifestations and gene mutations of Japanese xeroderma pigmentosum group A patients PMID:7577588
• Journal of the American Academy of Dermatology • 1994 • Siblings with xeroderma pigmentosum complementation group A with different skin cancer development: importance of sun protection at an early age PMID:7962783
• Mutation Research • 2001 • UV-induced skin carcinogenesis in xeroderma pigmentosum group A (XPA) gene-knockout mice with nucleotide excision repair-deficiency PMID:11376684

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