Recessive, but not dominant, mutations in peripheral myelin protein 22 gene show unique patterns of aggregation and intracellular trafficking.

A characteristic feature of mouse models of the peripheral neuropathies caused by dominant mutations in peripheral myelin protein 22 (pmp22) is the appearance, in Schwann cells, of pmp22 aggregates. Using a set of dominant and recessive pmp22 mutations that cause human disease of varying degrees of severity, we compared their potential for aggregation and trafficking patterns with those of wild-type pmp22. The potential for aggregation was assessed by determining the size distribution of the various pmp22 mutant proteins under conditions where wild-type pmp22 showed little or no aggregation. All disease-causing dominant mutations showed significant aggregation and failed to traffic to the cell surface. Although the position of the dominant mutation in the pmp22 molecule determined both its potential for aggregation and how far it trafficked in the cell, there was no correlation between aggregation and the severity of the disease. On the other hand, recessive mutations were uniquely distinguished from dominant mutations by both the low potential for aggregation and their trafficking to the cell surface. In the course of these studies, it was also noted that the potential for aggregation and the trafficking of mutant pmp22s is influenced by the nature and/or location of the epitope tag.