Accelerated accumulation of somatic mutations in mice deficient in the nucleotide excision repair gene XPA

Inheritable mutations in nucleotide excision repair (NER) genes cause cance r-prone human disorders, such as xeroderma pigmentosum, which are also char acterized by symptoms of accelerated ageing. To study the impact of NER def iciency on mutation accumulation iN vivo, mutant frequencies have been dete rmined in liver and brain of 2-16 month old NER deficient XPA(-/-), lacZ hy brid mice. While mutant frequencies in liver of 2-month old XPA(-/-), lacZ mice were comparable to XPA (+/-), lacZ and the lacZ parental strain animal s, by 4 months of age mutant frequencies in the XPA-deficient mice were sig nificantly increased by a factor of two and increased further until the age of 16 months. In brain, mutant frequencies were not found to increase with age, These results show that a deficiency in the NER gene XPA causes an ac celerated accumulation of somatic mutations in Liver but not in brain. This is in keeping with a higher incidence of spontaneous liver tumors reported earlier for XPA(-/-) mice after about 15 months of age.