Clinical and cellular characterization of two novel MPZ mutations, p.I135M and p.Q187PfsX63

ObjectivesWe report the clinical and cellular phenotypes of two novel MPZ mutations associated with CMT1B.MethodsThe two families were evaluated clinically, electrophysiologically, and genetically. The wild-type and mutant P0 fused with fluorescent proteins were expressed in vitro to monitor their intracellular trafficking. Adhesion assay was also performed to evaluate the adhesiveness of cells.ResultsThe two novel heterozygous MPZ mutations, p.I135M and p.Q187PfsX63, are associated with a childhood-onset demyelinating polyneuropathy. The median motor nerve conduction velocities of the two index patients carrying each mutation were 12.9 and 13.6 m/s, respectively. Fluorescence analysis demonstrated that the P0 I135M protein was located on the cell membrane, but the P0 Q187PfsX63 protein was retained ectopically in the endoplasmic reticulum and Golgi apparatus. Adhesion assay demonstrated a defective adhesiveness of cells expressing either mutant P0 protein, and P0 Q187PfsX63 had a more prominent defect of self-adhesive ability than P0 I135M.ConclusionsThis study expanded the spectrum of the MPZ mutations and revealed two disparate mechanisms of MPZ mutations associated with a typical CMT1B phenotype. Other modifying genetic, epigenetic, or environmental factors on CMT1B may exist to explain the discrepancy between the cellular phenotypes.