View PDF Version - RePub - Erasmus Universiteit Rotterdam

DNA repair and transcription are also intimately linked in a third human NER
syndrome, the photosensitive form of the pleiotropic disorder trichothiodystrophy
(TTD). The disease is very reminiscent of CS, including neurodevelopmental and
skeletal abnormalities and remarkable absence of skin cancer [5,11]. In addition,
TTD patients display ichthyosis (scaling of the skin) and the typical brittle hairs and
nails, which are due to a specific defect in expression of the group of cysteine-rich
matrix proteins. Most patients have point mutations in the XPD gene [12], which is
also involved in patients with XP [13] and in patients with combined features of XP
and CS [14]. A clue to the extreme clinical heterogeneity associated with mutations
in XPD, was the discovery that the gene encodes one of the heliease subunits of the
multi-protein TFIIH complex [IS]. TFIIH is involved in local unwinding of the
DNA helix around the lesion in NER [16] and of the promoter region in
transcription initiation of RNA polymerase II [17]. Thus, XPD mutations may not
only impair NER, causing photosensitivity, but may also subtly affect the
transcription process, providing a rational for the non-repair phenotypes of TID
such as growth retardation and the reduced expression of cysteine-rich matrix
proteins in TID hair
[18,19]. To obtain insight into the pathophysiology of the TID syndrome and to
study the molecular intricacies of repair and transcription in vivo we developed a
mouse model for TID by mimicking the causative point mutation of a
photosensitive TID patient in the mouse XPD gene (XPD R722w ). TID mice display
a remarkable resemblence to the human disease including brittle hair and ichthyosis
[20]. A partial NER defect was associated with mild UV sensitivity in cultured
fibroblasts but sUlprisingly also with a hitherto unnoticed predisposition to UVinduced
skin cancer (de Boer et af., submitted). Here we report that TTD mice
reveal a consistent picture of coherent features of premature aging. In addition to
reduced life span and cachectic dwarfism, TID mice display osteoporosis,
Figure 1. Aged appearance ofTTD mice. Progeroid symptoms (cachexia, kyphosis) appear at age 3-4
months but become more pronounced later in lite. The picture shows a TTD mouse of 16 months old.
Premature aging in TID mice 107