Glycoprotein Causes Charcot-Marie-Tooth–like Neuropathy in Transgenic Mice

In peripheral nerve myelin, the intraperiod line results from compaction of the extracellular space due to homophilic adhesion between extracellular domains (ECD) of the protein zero (P 0 ) glycoprotein. Point mutations in this region of P 0 cause human hereditary demyelinating neuropathies such as CharcotMarie-Tooth. We describe transgenic mice expressing a full-length P 0 modified in the ECD with a myc epitope tag. The presence of the myc sequence caused a dysmyelinating peripheral neuropathy similar to two distinct subtypes of Charcot-Marie-Tooth, with hypomyelination, altered intraperiod lines, and tomacula (thickened myelin). The tagged protein was incorporated into myelin and was associated with the morphological abnormalities. In vivo and in vitro experiments showed that P 0 myc retained partial adhesive function, and suggested that the transgene inhibits P 0 -mediated adhesion in a dominant-negative fashion. These mice suggest new mechanisms underlying both the pathogenesis of P 0 ECD mutants and the normal interactions of P 0 in the myelin sheath.