A temperature-sensitive disorder in basal transcription and DNA repair in humans

The xeroderma pigmentosum group D (XPD) helicase subunit of TFIIH functions in DNA repair and transcription initiation(1,2). Different mutations in XP D give rise to th ree ultraviolet-sensitive syndromes: the skin cancer-pron e disorder xeroderma pigmentosum (XP). in which repair of ultraviolet damag e is affected; and the severe neurodevelopmental conditions Cockayne syndro me (CS) and trichothiodystrophy (TTD). In the latter two, the basal transcr iption function of TFIIH is also presumed to be affected(3-5). Here we repo rt 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 th ermo-instability of TFIIH. Our findings reveal the clinical consequences of impaired basal transcription and mutations in very fundamental processes i n humans, which previously were only known in lower organisms.