The xeroderma pigmentosum group D (XPD) helicase subunit of TFIIH functions in DNA repair and transcription initiation. Different mutations in XPD give rise to three ultraviolet-sensitive syndromes: the skin cancer-prone disorder xeroderma pigmentosum (XP), in which repair of ultraviolet damage is affected; and the severe neurodevelopmental conditions Cockayne syndrome (CS) and trichothiodystrophy (TTD). In the latter two, the basal transcription function of TFIIH is also presumed to be affected. Here we report four unusual TTD patients with fever-dependent reversible deterioration of TTD features such as brittle hair. Cells from these patients show an in vivo temperature-sensitive defect of transcription and DNA repair due to thermo-instability of TFIIH. Our findings reveal the clinical consequences of impaired basal transcription and mutations in very fundamental processes in humans, which previously were only known in lower organisms.

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Keywords *Mutation, 0 (DNA, Complementary), 0 (Proteins), 130067-74-2 (ERCC-2 protein), Base Sequence, Cells, Cultured, DNA Repair/*genetics, DNA, Complementary/genetics, Female, Fever/pathology, Hair Diseases/*genetics/metabolism/pathology, Hair/metabolism/pathology, Human, Infant, Proteins/*genetics, Support, Non-U.S. Gov't, Support, U.S. Gov't, P.H.S., Syndrome, Temperature
Persistent URL dx.doi.org/10.1038/85864, hdl.handle.net/1765/3182
Citation
Vermeulen, W., Rademakers, S., Jaspers, N.G.J., Appeldoorn, E., Raams, A., Klein, B., … Kleijer, W.J.. (2001). A temperature-sensitive disorder in basal transcription and DNA repair in man. Nature Genetics, 27(3), 299–303. doi:10.1038/85864