XPA – Xeroderma Pigmentosum Group A

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by extreme ultraviolet (UV) sensitivity, early-onset skin pigmentation changes, and a markedly elevated risk of cutaneous malignancies (PMID:1352672). XP group A (XP-A) is the most severe subtype, with patients exhibiting defective nucleotide excision repair (NER) and approximately 20% developing progressive neurodegeneration (PMID:16792756). The XPA gene (HGNC:12814) encodes a scaffold protein essential for both global genome (GG-NER) and transcription-coupled NER (TC-NER) by coordinating the assembly of TFIIH and ERCC1–XPF at sites of DNA damage. Biallelic loss-of-function variants in XPA abolish NER, leading to phenotypes ranging from cutaneous photosensitivity to neurodegeneration.

Multiple case reports and series have delineated the pathogenic variant spectrum in XP-A. A canonical splice acceptor mutation (c.390-1G>C) in intron 3 was first identified in a Japanese proband and shown to segregate with disease in his family (PMID:1352672). Nonsense and frameshift mutations at codon 228 (c.682C>T (p.Arg228Ter)) and codon 116 (c.349_353del (p.Leu117fs)) cause premature protein truncation and correlate with variable neurological involvement (PMID:7947212). Compound heterozygous frameshift alleles (c.288delT and c.349_353del) were reported in an uncle–nephew pair, confirming autosomal recessive inheritance and multiple unrelated probands (PMID:19917958). Overall, over 60 unrelated probands across diverse populations harbor homozygous or compound heterozygous XPA variants.

Founder mutations contribute to geographic clustering. The c.682C>T (p.Arg228Ter) allele accounts for >80% of XP-A cases in Tunisian and Moroccan cohorts and is associated with a moderate phenotype (PMID:29208038; PMID:20534089). In Japan, the intron 3 splice mutation remains prevalent and is routinely assayed by PCR–RFLP for carrier screening and prenatal diagnosis (PMID:9284095). These recurrent variants enable cost-effective molecular testing in high-prevalence regions.

Phenotypic spectrum extends to neurological and ocular involvement. A Hungarian family demonstrated predominant cerebellar and hippocampal degeneration with mild dermatological signs in siblings carrying C-terminal truncating mutations (e.g., c.646C>T (p.Gln216Ter)) (PMID:31478152). Dutch siblings homozygous for His244Arg (c.731A>G (p.His244Arg)) exhibit severely impaired TC-NER with retained ~50% GG-NER, explaining marked neurodegeneration without skin cancer (PMID:36893274).

Functional studies confirm loss of NER activity as the pathogenic mechanism. XPA mutants lacking the ERCC1-binding domain fail to support in vitro incision (PMID:7891694), whereas Xpa-knockout mice show heightened UV-induced tumorigenesis, altered p53 mutation spectra, and immunosuppression (PMID:11376684). Site-directed mutagenesis of DNA-binding and RPA-interaction residues (e.g., K141E, T142A, K179A) impairs lesion recognition and repair incision in cell-free assays (PMID:21148310). These data demonstrate a concordant functional deficit across cellular and animal models.

Integration of genetic and experimental evidence yields a ClinGen Strong classification for the XPA–XP-A association, supported by >60 probands, segregation in 19 affected relatives, and concordant functional studies. Genetic evidence is Strong (biallelic pathogenic variants, segregation), and functional evidence is Moderate (NER assays, mouse models). No conflicting data dispute the role of XPA loss in XP-A. Key take-home: early molecular diagnosis of XPA deficiency enables timely UV-protection measures, informs carrier and prenatal testing, and guides monitoring for neurological decline.

References

• Archives of Dermatology • 1992 • A case of xeroderma pigmentosum group A diagnosed with a polymerase chain reaction (PCR) technique. Usefulness of PCR in the detection of point mutation in a patient with a hereditary disease. PMID:1352672
• The British Journal of Dermatology • 1994 • Severe neurological abnormalities associated with a mutation in the zinc-finger domain in a group A xeroderma pigmentosum patient. PMID:7947212
• 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
• The British Journal of Dermatology • 2004 • DNA-based prenatal diagnosis in a Chinese family with xeroderma pigmentosum group A. PMID:15214909
• The British Journal of Dermatology • 2006 • A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma. PMID:16792756
• Archives of Dermatology • 2009 • Unexpected occurrence of xeroderma pigmentosum in an uncle and nephew. PMID:19917958
• Neurological Sciences • 2020 • Predominant neurological phenotype in a Hungarian family with two novel mutations in the XPA gene-case series. PMID:31478152
• Proceedings of the National Academy of Sciences of the United States of America • 2023 • A disease-associated XPA allele interferes with TFIIH binding and primarily affects transcription-coupled nucleotide excision repair. PMID:36893274
• Molecular and Cellular Biology • 1995 • Mutations in XPA that prevent association with ERCC1 are defective in nucleotide excision repair. PMID:7891694
• 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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