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A point of concern in the extrapolation of data obtained from mouse mutants to
humans are the significant (interspecies) physiologic differences (metabolic rate,
certain DNA repair characteristics, genotoxic pressure, life span), which could
exaggerate or underestimate the importance of celiain physiologic parameters. A
clear example are the manifestations of neurological features in the murine models
(both neurodegeneration in XP as well as neurodysmyelination in CS and TID),
which are, if present at all, much milder compared to the human situation. Probably,
in the mouse there is simply not enough time for some clinical manifestations to
arise, particularly when time is a critical factor in their onset. Alternatively, the time
scale between man and mouse is different. Compare for instance the mean age of
onset of UV-induced tumors, which is 8 years in XP patients [18] but only 3 to 4
months in XPA mice [19]. The (repair-deficient) mouse latency periods may reach
the minimal time intrinsic to the process.
Mice are genetically well defined and allow proper comparison because other
genetic differences perturbing any comparison are eliminated. Thus, when the effect
of the specific genetic mutation is dominant over the specific genetic constitution
the studies with inbred strains are very informative. This certainly applies to the
very rare human NER-syndromes for which a relatively small number of clinical
reports can establish a dogma for the syndrome. Using NER-deficient mouse
models, large-scale experiments and manipulation of experimental conditions may
reveal subtle but clinically and scientifically relevant information (e.g. tumor
susceptibility of CSB and TID mice). However, the use of genetically inbred mouse
strains needs consideration. Since the genetic make-up and consequently relevant
physiologic parameters of different strains of laboratory mice varies this may have
significant influence on e.g. tumor incidence and spectrum. Therefore, it is wise to
study Clucial parameters in more than one genetic background to exclude a possible
bias derived from the specific genetic constitution.
Another very promising potential of mice is the ability to search for synergistic
effects of genetic loci and pathways by simple genetic means, as it has been
successfully applied in yeast and Drosophila models. Moreover, manipulation of the
mouse genome is becoming more and more sophisticated, offering increased
versatility and utility of the mouse as the in vivo system amenable to experimental
analysis. In conclusion, we are only at the very beginning of the full exploitation of
the DNA repair deficient mice for various important areas of science including
carcinogenesis, aging, development, genotoxicity testing and mutagenesis.
NER-deficient mouse models 43