Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XP-D patients

Mutations in the XPD gene result in xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), the phenotypes of which are often intricate. To understand the genotype/phenotype relationship, we engineered recombinant TFIIHs in which XPD subunits carry amino acid changes found in XPD patients. We demonstrate that all the XPD mutations are detrimental for XPD helicase activity, thus explaining the NER defect. We also show that TFIIH from TTD patients, but not from XP patients, exhibits a significant in vitro basal tran- scription defect in addition to a reduced intracellular concentration. Moreover, when XPD mutations pre- vent interaction with the p44 subunit of TFIIH, transactivation directed by certain nuclear receptors is in- hibited, regardless of TTD versus XP phenotype, thus explaining the overlapping symptoms. The implications of these mutations are discussed using a structural model of the XPD protein. Our study provides explana- tions for the nature and the severity of the various clinical features.