Inherited demyelinating peripheral neuropathies: relating myelin packing abnormalities to P0 molecular defects.

P0-glycoprotein, the major integral membrane protein of peripheral nerve myelin, is thought to mediate myelination and membrane interactions via its extracellular domain (P0-ED). Molecular modeling of P0-ED has suggested which of its amino acid side-chains may be involved in heterophilic and homophilic adhesions. We previously showed that some of these amino acids are the same ones that are substituted or deleted due to mutations in the human gene for P0 (MPZ), which correlate with certain cases of demyelinating motor and sensory peripheral neuropathies. In the current study, high magnification electron microscopy was used to examine the myelin membrane packing in sural nerve biopsies from patients with MPZ mutations. We found that there were distinguishable ultrastructural phenotypes that could be explained by the alterations in P0-ED. These phenotypes, which were not observed in a control nerve, included widening or irregularity of the extracellular apposition alone (delta Ser34; Arg69Cys), widening at both the extracellular and cytoplasmic appositions (Arg69His), the presence of focal bridges in the widened extracellular space (Arg69His), and a diminished (Arg69Cys) or absence (Arg69His) of staining of the double intraperiod line. Our study, which suggests that the altered P0 is incorporated into the myelin sheath, provides a unique basis for further molecular/ultrastructural correlations between P0-ED structure and myelination irregularities.