Carcinogenesis Advance Access published online on August 4, 2005
Carcinogenesis, doi:10.1093/carcin/bgi204
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1 Basic Research Laboratory, CCR, NCI, Bethesda, MD
* To whom correspondence should be addressed. 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 (QRT-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 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.
Received June 7, 2005
Revised July 25, 2005
Accepted July 28, 2005
CANCER BIOLOGY
Reduced XPC DNA repair gene mRNA levels in clinically normal arents of xeroderma pigmentosum patients
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2 Basic Research Laboratory, CCR, NCI, Bethesda, MD; Present Address: Washington and Lee Law School, Lexington, VA
3 Armed Forces Institute of Pathology, Washington, DC
4 Basic Research Laboratory, CCR, NCI, Bethesda, MD; Present Address: Kinki University School of Medicine, Osaka, Japan
5 Basic Research Laboratory, CCR, NCI, Bethesda, MD; Present Address: Georg-August-University, Goettingen, Germany (Partially supported by a grant from the Deutsche Forschungsgemeinschaft)
6 Laboratory of Cellular Oncology, CCR, NCI, Bethesda, MD; Present Address: University of North Carolina, Chapel Hill, NC
7 Laboratory of Cellular Oncology, CCR, NCI, Bethesda, MD
8 Basic Research Laboratory, CCR, NCI, Bethesda, MD; Department of Dermatology, Brown Medical School, Providence, R.I.
9 Basic Research Laboratory, CCR, NCI, Bethesda, MD; Present Address: University of California School of Medicine, Los Angeles, CA
10 Department of Dermatology, Yüzüncüyil University Medical School, Van, Turkey
11 Department of Biochemistry, Inönü University Medical School, Malatya, Turkey
12 Department of Human Genetics, Tel Aviv University Medical School, Tel Aviv, Israel
13 Laboratory of Genetic Instability and Cancer, UPR2169 CNRS, Institute Gustave Roussy, Villejuif, France
Kenneth H. Kraemer, E-mail: kraemerk{at}nih.gov
Abstract Deceased
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