GENETIC-HETEROGENEITY OF THE EXCISION REPAIR DEFECT ASSOCIATED WITH TRICHOTHIODYSTROPHY

Trichothiodystrophy (TTD) is a rare autosomal recessive disease charac terized by brittle hair with reduced sulfur content, mental and physic al retardation, a peculiar face and ichthyosis. Photosensitivity has b een reported in approximately 20% of the cases in the literature. DNA repair investigations demonstrated that clinical photosensitivity is u sually associated with an enhancement of the cellular UV-sensitivity a nd that the repair defect is in the same gene as in patients from grou p D of xeroderma pigmentosum (XP). In this paper we describe the chara cterization of 13 further TTD patients; a defect in the nucleotide-exc ision repair was observed in fibroblast strains from 10 patients, conf irming that TTD is frequently associated with DNA repair defects. Gene tic analysis based on complementation studies demonstrated the presenc e of the XP-D defect in seven repair-defective TTD cases, indicating d efinitively that the concurrence of TTD with XP-D is not a sporadic or casual event. However, three further cell strains (TTD4VI and TTD6VI from two French siblings and TTD1BR from an English patient) showed re storation of normal UV-induced DNA repair synthesis after fusion with XP or TTD cells belonging to XP group D. These observations, which giv e the first indication that TTD is associated with repair defects beha ving differently in the functional test of complementation, suggest so me kind of causal connection between defective excision-repair factors and clinical features diagnostic for TTD. A peculiar aspect of TTD in which repair deficiencies are not related to an increased susceptibil ity to cancer is confirmed also in all the repair-defective TTD patien ts investigated in this paper.