Phenotypic differences between peripheral myelin protein-22 (PMP22) and myelin protein zero (P0) mutations associated with Charcot-Marie-Tooth-related diseases

Mutations in the genes for peripheral myelin protein-22 (PMP22) and myelin protein zero (P-0) cause human hereditary neuropathies with varying clinical and pathological phenotypes. In this study, we examine the effects of representative disease-causing mutations on the subcellular distribution of their corresponding PMP22- and P-0-enhanced green fluorescent protein (EGFP) fusion proteins. In transiently transfected HeLa and 293 cells, we find that wild-type P-0-EGFP and PMP22-EGFP are efficiently synthesized and transported through the secretory pathway to the plasma membrane. The P-0-EGFP and PMP22-EGFP mutants can be classified into several groups: those that are transported to the plasma membrane as in the majority of P-0 mutants; those that are retained in the endoplasmic reticulum as in the majority of PMP22 mutants; and those that are a mixture of the two. In addition, several of these disease-causing mutations are associated with the development of abnormal intracellular cytoplasmic structures that we have previously identified as either intracellular myelin figures or aggresomes. Our studies indicate that different types of PMP22 and P-0 mutations are associated with specific intracellular chaperone proteins, including calnexin and BiP, and that these associations can be altered by glycosylation. These findings indicate that the various P-0 and PMP22 mutants may exert their pathogenic effects in different subcellular compartments and by different mechanisms in the mammalian cell.