Functional abnormalities in P0-deficient mice resemble human hereditary neuropathies linked to P0 gene mutations.

Mutations in the gene encoding the transmembranous cell adhesion molecule, myelin protein zero (P0), have been reported in patients with Charcot-Marie-Tooth disease types 1B and 3 (Déjérine-Sottas disease). We have previously shown that the targeted deletion of the P0 gene in mice results in impairment of sciatic nerve conduction, and we now extend our detailed electrophysiologic investigation to the facial nerve. In concordance with histologic investigations which revealed severe hypomyelination in peripheral nerves we found the typical electrophysiologic signs of severe dysmyelination in both the facial and sciatic nerves in mice homozygously deficient for the expression of P0 (P0 -/- mice). As compared to control mice (P0+/+), nerve conduction velocities were reduced to below 10% and compound muscle action potential (CMAP) amplitudes to below 25%, while CMAP duration and excitation thresholds were markedly increased. Surprisingly, nerve conduction changes in mice heterozygously deficient for P0 (P0+/-) were only mild, were detected only in the sciatic nerve, and occurred not before 5-7 months of age. They were more prominent at age 12-13 months. Thus, P0 -/- mice resemble severe human inherited neuropathies like Charcot-Marie-Tooth disease type 3 (Déjérine-Sottas disease) with onset early in life, whereas the P0 +/- mice may resemble the milder form, CMT1B.