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SYMPTOMS OF PREMATURE AGING IN A MOUSE MODEL FOR THE
DNA REPAIR/BASAL TRANSCRIPTION SYNDROME
TRICHOTHIODYSTROPHY
.IAN DE BOER I , JAN HUJJMANS', WIEBEKE VAN LEEUWEN 3 , AXEL THEMMEN',
HANS MORREAU 5 , MORTEZA MERADJI 6 , GEERT WEEDA I AND JAN H..I.
HOEJJMAKERS I .
IMGC-Dept. a/Cell Biolog)! and Genetics, Erasllllls University Rotterdam, P.G. Box J 738.
3000 DR Rotterdam, The Netherlallds; lMGe-Dept. a/Clillical GClletics, EJ'{{slI1us University
Rotlerdalll, Rotterdam, The Netherlands; 3Dept. a/Experimental Radiology, Eras/llus
UniversiZv RottCl'dalll, Rotterdam, The Netherlallds; 4Dept. a/Endocrillologyand
Reproduction, EraslIIlls University Rotterdam, Rotterdam, The Netherlallds; 5Dept. of
Pathology, Leiden Ulliversify Medical Centre, P.O. Box 9600,2300 Re, Ieidell, The
Netherlands: 6j)ept. a/Radiology, Sophia KillderziekclI!Jlds, Rollen/alll, The Netherlands.
The sun-sensitive form of the severe neurodevclopl11cntal, 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 TFIlH. The
complcx disease phenotype is hypothesized to be in part derived from a repair defect causing
UV sensitivity and in part from a subtle, viable basal transcription deficiency accounting for
the other TTD features. Previously we established a TTD mouse model by mimicking the
causative XPD point-mutation of a photosensitive TTD patient. TID mice reflect to a
remarkable extent the pleiotlOpie features of the human disorder. In this report we describe a
comprehensive range of progeroid symptoms observed in aging TTO mice. These include
reduced life span and fertility, cachectic dwarfisl11, carly graying, sebaceous gland
hyperplasia, spinal kyphosis and osteoporosis, reminiscent of human aging. TTD mice reveal
an important link between DNA repair and transcription capacity in the onset of age-related
symptoms.
manuscript in preparation