Article abstract
Nature Neuroscience 10, 1414 - 1422 (2007)
Published online: 21 October 2007 | doi:10.1038/nn1990
Neurological defects in trichothiodystrophy reveal a coactivator function of TFIIH
Emmanuel Compe1, Monica Malerba1,3, Luc Soler2, Jacques Marescaux2, Emiliana Borrelli1,3 & Jean-Marc Egly1,2
Abstract
Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH yield the rare genetic disorder trichothiodystrophy (TTD). Although this syndrome was initially associated with a DNA repair defect, individuals with TTD develop neurological features, such as microcephaly and hypomyelination that could be connected to transcriptional defects. Here we show that an XPD mutation in TTD mice results in a spatial and selective deregulation of thyroid hormone target genes in the brain. Molecular analyses performed on the mice brain tissue demonstrate that TFIIH is required for the stabilization of thyroid hormone receptors (TR) to their DNA-responsive elements. The limiting amounts of TFIIH found in individuals with TTD thus contribute to the deregulation of TR-responsive genes. The discovery of an unexpected stabilizing function for TFIIH deepens our understanding of the pathogenesis and neurological manifestations observed in TTD individuals.
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, C.U. Strasbourg, France.
- Institut de Recherche sur les Cancers de l'Appareil Digestif, 1 Place de l'Hôpital, F-67091 Strasbourg, France.
- Present address: Department of Psychiatry and Human Behavior, 3113 Gillespie Neuroscience, University of California, Irvine, California, USA.
Correspondence to: Emiliana Borrelli1,3 e-mail: borrelli@uci.edu
Correspondence to: Jean-Marc Egly1,2 e-mail: egly@titus.u-strasbg.fr
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