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XPD mutations inhibit TFIIH-dependent transactivation mediated by vitamin D receptor in trichothiodystrophy fibroblasts

Tuesday, October 25, 2011 — Poster Session II

Noon – 2:00 p.m.

Natcher Conference Center




  • S Khan
  • X Zhou
  • D Tamura
  • E Compe
  • J Egly
  • T Ueda
  • J Boyle
  • J DiGiovanna
  • K Kraemer


Inherited mutations in XPD gene cause trichothiodystrophy (TTD), a rare autosomal-recessive disorder with sulfur-deficient brittle hair and developmental abnormalities without skin cancer. Xeroderma pigmentosum (XP), a rare genetic-disease with increased risk of skin cancer, may also arise from XPD gene mutations. XPD is a structural bridge tying basal transcription factor IIH (TFIIH) core with cdk-activating kinase (CAK) complex which phosphorylates nuclear receptors. The TTD phenotypes can be explained by unique functions of XPD gene besides its role in DNA repair. We studied TFIIH–dependent transactivation by nuclear receptor for vitamin D (VDR) and thyroid (TR) in 5 patients with XPD gene mutations but different clinical phenotypes: 2 TTD (TTD354BE, TTD412BE), 2 XP (XP29BE, XP34BE) and 1 combined XP/TTD (XPTTD306BE). Quantitative real-time RT-PCR revealed a significant (p < 0.05) decrease in vitamin D induction ratio of VDR-responsive genes CYP24 and osteopontin in fibroblasts from TTD patients compared to XP and normal controls. Interestingly, basal expression of CYP24, osteopontin, and KLF9 (a TR responsive gene) was elevated in TTD cells. These results indicate that nuclear receptor-mediated transactivation is greatly reduced in TTD compared to XP and normal cells. These differences may contribute to the different clinical-phenotypes in TTD and XP patients.

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