A stop codon in xeroderma pigmentosum group C families in Turkey and Italy: Molecular genetic evidence for a common ancestor

Xeroderma pigmentosum family G from Van, Turkey had two severely affected c hildren: a son with multiple skin cancers who died at age 10 (XP67TMA), and an 8 y old daughter who began developing skin cancer before 3 y of age (XP 68TMA). XP67TMA and XP68TMA cells were hypersensitive to killing by ultravi olet and the post-ultraviolet DNA repair level was 12-16% of normal. Host c ell reactivation of an ultraviolet-treated reporter plasmid cotransfected w ith a vector expressing wild-type XPC cDNA assigned XP67TMA to xeroderma pi gmentosum complementation group C. The XPC mRNA level was markedly reduced. Sequencing of the 3.5 kb XPC cDNA from XP67TMA showed a C-T mutation in XP C exon 8 at base pair 1840. This mutation converts the CGA codon of arginin e at amino acid 579 to a UGA stop codon resulting in marked truncation of t he 940 amino acid xeroderma pigmentosum C protein. Restriction fragment len gth polymorphism analysis of XPC exon 8 DNA in XP67TMA and XP68TMA showed t hat both affected children had a homozygous mutation and that both parents had heterozygous normal and mutated sequences at the same position consiste nt with a history of consanguinity in the family. The mutated allele also c ontained two XPC single nucleotide polymorphisms. The same mutated XPC alle le was reported in an Italian family. Studies of 19 microsatellite markers flanking the XPC gene on chromosome 3 suggest that the XPC allele passed be tween Italy and Turkey approximately 300-500 y ago. This XPC allele contain ing a nonsense mutation is associated with severe clinical disease with mul tiple skin cancers and early death.