MOLECULAR AND CELLULAR ANALYSIS OF THE DNA-REPAIR DEFECT IN A PATIENTIN XERODERMA-PIGMENTOSUM COMPLEMENTATION GROUP-D WHO HAS THE CLINICAL-FEATURES OF XERODERMA-PIGMENTOSUM AND COCKAYNE-SYNDROME

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are quite distin ct genetic disorders that are associated with defects in excision repa ir of UV-induced DNA damage. A few patients have been described previo usly with the clinical features of both disorders. In this paper we de scribe an individual in this category who has unusual cellular respons es to UV light. We show that his cultured fibroblasts and lymphocytes are extremely sensitive to irradiation with UV-C, despite a level of n ucleotide excision repair that is 30%-40% that of normal cells. The de ficiency is assigned to the XP-D complementation group, and we have id entified two causative mutations in the XPD gene: a gly-->arg change a t amino acid 675 in the allele inherited from the patient's mother and a -1 frameshift at amino acid 669 in the allele inherited from his fa ther. These mutations are in the C-terminal 20% of the 760-amino-acid XPD protein, in a region where we have recently identified several mut ations in patients with trichothiodystrophy.