Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients

Abstract

Xeroderma pigmentosum group C (XP-C) is a rare autosomal recessive disorder. Patients with two mutant alleles of the XPC DNA repair gene have sun sensitivity and a 1000-fold increase in skin cancers. Clinically normal parents of XP-C patients have one mutant allele and one normal allele. As a step toward evaluating cancer risk in these XPC heterozygotes we characterized cells from 16 XP families. We identified 15 causative mutations (5 frameshift, 6 nonsense and 4 splicing) in the XPC gene in cells from 16 XP probands. All had premature termination codons (PTC) and absence of normal XPC protein on western blotting. The cell lines from 26 parents were heterozygous for the same mutations. We employed a real-time quantitative reverse transcriptase-PCR assay as a rapid and sensitive method to measure XPC mRNA levels. The mean XPC mRNA levels in the cell lines from the XP-C probands were 24% (P<10(-7)) of that in 10 normal controls. This reduced XPC mRNA level in cells from XP-C patients was caused by the PTC that induces nonsense-mediated mRNA decay. The mean XPC mRNA levels in cell lines from the heterozygous XP-C carriers were intermediate (59%, P=10(-4)) between the values for the XP patients and the normal controls. This study demonstrates reduced XPC mRNA levels in XP-C patients and heterozygotes. Thus, XPC mRNA levels may be evaluated as a marker of cancer susceptibility in carriers of mutations in the XPC gene.

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual’s susceptibility to sporadic colorectal cancer

“…An important role of XPC C/A (i11) in carcinogenesis probably results from the fact that the XPC intron 11 splice acceptor site polymorphism is related to an increased frequency of exon 12 skipping, leading thus to diminished DNA repair. Khan et al reported that the homozygous variant A/A is associated with an approximately 50% reduction in DNA repair capacity (DRC) of the XPC protein [52]. This is consistent with the observations by Lopez-Cima et al, who found that the PAT+/33512C(939Gln) /intron11A haplotype contributed to reduced DNA repair capacity and thus, to an increased risk of lung cancer [53].…”

High frequency of the V548A fs X572 XPC mutation in Tunisia: implication for molecular diagnosis

“…As previous studies of XP-C showed that Moroccan, Algerian and Italian patients had the V548A fsX572 XPC mutation, [10][11][12][13]18 patients were screened for this mutation. All investigated patients bear this mutation.…”

“…The V548A fsX572 mutation was previously described in three unrelated families from Italy, Algeria and Morocco, and also with a compound heterozygous XPC mutation in Honduras and USA patients. [10][11][12][13] To elucidate the spectrum of XPC gene mutations, 20 Tunisian patients with an XP severe clinical form were analyzed. We report here the relatively homogeneous mutation spectrum of the XPC gene in Tunisian patients and discuss its implication for molecular diagnosis of XP-C in North Africa.…”

Clinical utility gene card for: Xeroderma pigmentosum

“…Here, a phenotype correlation emerges indicating that XPC mutations only result in a classical XP phenotype. [5][6][7][8] XPD/ERCC2: 48 known disease-causing mutations from 32 XP patients (36 trichothiodystrophy patients are excluded). Mutations: 43 (90%) base exchanges and 5 (10%) deletions.…”

“…This holds true only for XPC but not the other XP genes. 5,6 3.1.2 Describe the burden of alternative diagnostic methods to the patient The burden of skin punch biopsies is very low for the patients (bleeding, possibly infection, and pain) and will result in a tiny scar. The burden of drawing venous blood is negligible.…”