Clinical, cellular, and molecular features of an Israeli xeroderma pigmentosum family with a frameshift mutation in the XPC gene: Sun protection prolongs life

An Ashkenazi Jewish Israeli family with two children affected with severe x eroderma pigmentosum was investigated, A son, XP12TA, developed skin cancer at 2 y and died at 10 y. A daughter, XP25TA, now 24 y old, was sun protect ed and began developing skin cancers at 10 y. Their cultured skin fibroblas ts showed reductions in post-ultraviolet survival (11% of normal), unschedu led DNA synthesis (10% of normal), global genome DNA repair (15% of normal) , and plasmid host cell reactivation (5% of normal). Transcription-coupled DNA repair was normal, however, Northern blot analysis revealed greatly red uced xeroderma pigmentosum complementation group C mRNA, A plasmid host cel l reactivation assay assigned the cells to xeroderma pigmentosum complement ation group C, Cells from both parents and an unaffected child exhibited no rmal post-ultraviolet-C survival and normal DNA repair. Sequencing the xero derma pigmentosum complementation group C cDNA of XP12TA and XP25TA reveale d a homozygous deletion of two bases (del AT 669-670) in exon 5 with a new termination site 10 codons downstream that is expected to encode a truncate d xeroderma pigmentosum complementation group C protein. Sequence analysis of the xeroderma pigmentosum complementation group C cDNA in cells from the parents found identical heterozygous mutations: one allele carries both th e exon 5 frameshift and an exon 15 polymorphism and the other allele carrie s neither alteration. Cells from the unaffected brother had two normal xero derma pigmentosum complementation group C alleles, This frameshift mutation in the xeroderma pigmentosum complementation group C gene led to reduced D NA repair with multiple skin cancers and early death. Sun protection delaye d the onset of skin cancer and prolonged Life in a sibling with the same mu tation.