Journal Article

Reduced <i>XPC</i> DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients

Sikandar G. Khan, Kyu-Seon Oh, Tala Shahlavi, Takahiro Ueda, David B. Busch, Hiroki Inui, Steffen Emmert, Kyoko Imoto, Vanessa Muniz-Medina, Carl C. Baker, John J. DiGiovanna, Deborah Schmidt, Arash Khadavi, Ahmet Metin, Engin Gozukara, Hanoch Slor, Alain Sarasin and Kenneth H. Kraemer

in Carcinogenesis

Volume 27, issue 1, pages 84-94
Published in print January 2005 | ISSN: 0143-3334
Published online August 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi204
Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients

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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.

Keywords: CypE, cyclophilin E; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GGR, global genomic repair; HCR, host cell reactivation; NER, nucleotide excision repair; NMD, nonsense-mediated mRNA decay; PTCs, premature termination codons; QRT–PCR, quantitative reverse transcriptase–PCR; UDS, unscheduled DNA synthesis; XP, Xeroderma pigmentosum; XP-C, Xeroderma pigmentosum group C

Journal Article.  7576 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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