We are creating transgenic mouse models of hereditary motor and sensory neuropathy to address pathogenethic questions. First, we are testing the hypothesis that some Po mutations act through gain of function, by expressing a CMT1b mutation, delSer34, in addition to two normal copies of Po. We have shown previously that overexpression of wild type Po causes dysmyelination in a dose‐dependent fashion. Less than 50% overexpression of Po protein produces no effect, whereas higher overexpression causes severe dysmyelination. We have produced 5 lines of delSer34 transgenic mice that express the transgene at different levels, ranging from 5% to 300% of wild type Po. Lines that express Po delSer34 below the 50% threshold show abnormal myelin sheaths containing metachromatic material in semithin sections. Lines that express above the 50% threshold show positive signs characteristic of CMT1b, like “onion bulbs,” together with signs typical of wildtype Po overexpression. These myelin sheath abnormalities and onion bulbs are specific to mutant Po, as they were never observed in mice overexpressing wildtype Po. These preliminary results suggest that CMT1b mutations may have their effect through a dominant negative or toxic mechanism. In one line, mutant Po expression is roughly 50% of wildtype Po, a level comparable with one normal Mpz allele. This line was crossed with heterozygous Po knock out mice to obtain a genotype (Po wt/−/PodelSer34) similar to that of a CMT1b patient. These mice represent a potential model of CMT1b.
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