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    Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients
    (Oxford Univ Press, 2006) Khan, SG; Oh, KS; Shahlavi, T; Ueda, T; Busch, DB; Inui, H; Emmert, S
    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.
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    Spectrum of mutations in 25 xeroderma pigmentosum complementation group C patients from the United States, Turkey and Israel
    (Blackwell Publishing Inc, 2002) Kraemer, KH; Khan, SG; Shahlavi, T; Busch, DB; Ueda, T; Inui, H; Emmert, S
    [Abstract Not Available]
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    Two essential splice lariat branchpoint sequences in one intron in a xeroderma pigmentosum DNA repair gene
    (Oxford Univ Press, 2004) Khan, SG; Metin, A; Gozukara, E; Inui, H; Shahlavi, T; Muniz-Medina, V; Baker, CC
    The lariat branch point sequence (BPS) is crucial for splicing of human nuclear pre-mRNA yet BPS mutations have infrequently been reported to cause human disease. Using an inverse RT-PCR technique we mapped two BPS to the adenosine residues at positions -4 and -24 in intron 3 of the human XPC DNA repair gene. We identified homozygous mutations in each of these BPS in two newly diagnosed Turkish families with the autosomal recessive disorder xeroderma pigmentosum (XP). Cells from two severely affected children in family A harbor a homozygous point mutation in XPC intron 3 (-9 T to A), located within the downstream BPS. Using a real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) assay, these cells expressed no detectable (<0.1%) normal XPC message. Instead they expressed an XPC mRNA isoform with deletion of exon 4 that has no DNA repair activity in a host cell reactivation (HCR) assay. In contrast, in cells from three mildly affected siblings in family B, the BPS adenosine located at the -24 position in XPC intron 3 is mutated to a G. Real-time QRT-PCR revealed 3-5% of normal XPC message. These cells from family B had a higher level of HCR than cells from the severely affected siblings in family A, who had multiple skin cancers. Mutations identified in two BPS of the XPC intron 3 resulted in alternative splicing that impaired DNA repair function, thus implicating both of these BPS as essential for normal pre-mRNA splicing. However, a small amount of normal XPC mRNA can provide partial protection against skin cancers.