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Table 3. Comparison of the TTDIBEL patient and TTD mice
TTD1BEL patient TTD mouse
Cutaneous Ichthyosis Acanthosis, hypergranulosis, hyperkeratosis
Brittle hair, reduced cysteine content Brittle hair, reduced CRP content
Development Failure to thrive, developmental
delay
NER
parameters
Died age 3 from respiratory infection
Hypogonadism, undescended testis
Impaired intelligence, cerebellar
atrophy
Very photosensitive skin; UDS 26%
of control; fibroblasts 1.5 times more
sensitive to UV; no skin cancer
Growth retardation, adipose tissue hypoplasia
Most die before age 1 year (mean 35 weeks)
Females reduced fertility, males normal
fertility
Occasional tremors, normal myelination of
nervus opliclis and /1, ischiaticlIS
More UV-sensitive skin than wild-type
mice; no acutc sensitivity to dermally
applied DMBA; UDS 25 % of conh'oI;
MEFs 1.5 times more sensitive to UV; skin
cancer prone (UV- and DMBA-induced)
from 1.3-fold to 2.3-fold compared to wt and 1O.6-fold for an XP-A fIbroblast line,
unpublished data). Also after in vivo exposure of TTD mice in a UV and a DMBA
carcinogenesis experiment, a remarkably mild response was noticed. Acute
sensitivity to dermally applied DMBA was strikingly lower in TTD mice compared
to the dramatic cutaneous lesions induced inXPA and CSB deficient mice (de Vries
et aI., 1995; van der Horst et aI., 1997). Similarly, in the UV carcinogenesis
experiment, XPA and CSB mice but not TID mice suffered from severe eye lesions
(Bowenoid lesions), pruritis and cutaneous scaling. Despite the low cytotoxicity
TTD mice appeared to be prone to UV- and DMBA- induced skin cancer
development in both experiments. A detailed analysis of skin carcinogenesis
susceptibility in TTD mice will be reported elsewhere (de Boer et ai, manuscript in
prep.). The relative insensitivity of TID mice may be due to a combination of two
factors: the altered skin morphology may provide some protection and the residual
repair may be predominantly used for transcription-coupled repair, that has a major
effect on UV survival. The latter is confirmed by the reduced residual UDS III
MEFs from TTD/CSB double mutant mice, that are totally defective in
transcription-coupled repair (unpublished results).
The TTD mouse as a model for non-repair features of the human disorder
The TTD phenotype is extremely pleiotropic (see Table 3) and involves many extra
features beyond those of XP-type XP-D patients. In addition to the NER defect and
XP characteristics such as photosensitivity and cancer predisposition, the TTD
mouse closely resembles the human disorder with regard to these other non-repair
A mouse model for TID 77