The sun-sensitive form of the severe neurodevelopmental, brittle hair disorder trichothiodystrophy (TTD) is caused by point mutations in the essential XPB and XPD helicase subunits of the dual functional DNA repair/basal transcription factor TFIIH. The phenotype is hypothesized to be in part derived from a nucleotide excision repair defect and in part from a subtle basal transcription deficiency accounting for the nonrepair TTD features. Using a novel gene-targeting strategy, we have mimicked the causative XPD point mutation of a TTD patient in the mouse. TTD mice reflect to a remarkable extent the human disorder, including brittle hair, developmental abnormalities, reduced life span, UV sensitivity, and skin abnormalities. The cutaneous symptoms are associated with reduced transcription of a skin-specific gene strongly supporting the concept of TTD as a human disease due to inborn defects in basal transcription and DNA repair.

0 (Proteins), 0 (Transcription Factors), 130067-74-2 (ERCC-2 protein), Animals, Cells, Cultured, DNA Repair/*genetics, Disease Models, Animal, Female, Gene Fusion, Growth/genetics/physiology, Hair Diseases/*genetics/mortality/physiopathology, Hair/abnormalities, Human, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mutagenesis, Site-Directed, Mutation/genetics, Proteins/genetics/physiology, Skin/metabolism/pathology, Support, Non-U.S. Gov't, Survival Analysis, Syndrome, Transcription Factors/genetics/physiology, Transcription, Genetic/genetics, Xeroderma Pigmentosum/genetics,
Molecular Cell
(see also minireview Cell 93, 1099-1102, 1998).
Erasmus MC: University Medical Center Rotterdam

de Boer, J, de Wit, J, van Steeg, H, Berg, R.J.W, Morreau, H, Visser, P, … Weeda, G. (1998). A mouse model for the basal transcription/DNA repair disorder trichothiodystrophy. Molecular Cell, 1(7), 981–990. doi:10.1016/S1097-2765(00)80098-2