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The TTD mouse and inborn defects in basal transcription
One of the motivations to generate a TTD mouse was to understand the role of the
basal transcription function of TFIIH in the onset of TTD features. We have
postulated, that the non-repair traits of TTD (and XP/CS) are due to a subtle
impairment of the XPD role in basal transcription (Bootsma and Hoeijmakers,
1993). To explain the characteristic hair and skin abnonnalities of TTD we have
proposed, that TTD-type XPD mutations may alter the XPD conformation and in
this way affect the stability of the TFIIH complex. Under normal conditions de novo
synthesis of TFlIH is thought to compensate for the reduced half-life. However, in
terminal differentiating tissues (see Figure 6) where de novo synthesis gradually
declines, the mutated TFIIH might get exhausted before the transcriptional program
has been complctcd (Hoeijmakers et aI., 1996). Indications for reduced levels of
TFIIH underlying the CS features associated with defects in TFIIH subunits XPB
and XPD have been reported by Satoh and Hanawalt (1997). In the hair this would
lead to diminished transcription of genes expressed late in terminal differentiation,
such as those for the abundantly expressed CRPs, that perfOlTIl the final crosslinking
between the keratin filaments, before hair keratinocytes dehydrate, enucleate
and become solid cuticle or cortex of the hair fiber (see Figure 6, left panel and
Powel and Rogers, 1994 for a review). Similarly, in terminal differentiation of the
skin, genes such as SPRR2, that encode cross linking components of the cOluified
envelope and are velY abundantly expressed late in tenninal differentiation (Figure
6, right panel), may suffer specifically from premature lack of TFlIH. Utilizing the
mouse model we have investigated SPRR2 expression in the TTD skin. Northelu
blot analysis revealed reduced SPRR2 transcript levels when compared with the
constitutively expressed 18S rRNA and EFla inRNA. Although the 2.5- to 3-fold
reduction in SPRR2 transcript levels may not seem dramatic, it is important to
realize that a comparable decrease in CRP levels (Table 1) is associated with the
dramatic hair phenotype. These findings link the skin symptoms with a transcription
problem and therefor we favour the model of a transcription insufficiency
underlying the TTD features. Whether this is entirely due to an intTinsic
transcription problem or whether there is an additional contribution from lesions,
triggering apoptosis or premature terminal differentiation (Yamaizumi and Sugano,
1994; Ljungman et aI., 1996) remains to be investigated. The TID mouse will be of
great value to further explore the surprising concept of human disorders in which
the fundamental basal transcription process is affected.
A mouse model for TID 79