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.

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Molecular Cell
Erasmus MC: University Medical Center Rotterdam

de Boer, J., de Wit, J., van Steeg, H., Berg, R., 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