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

OBJECTIVES

We report the clinical and cellular phenotypes of two novel MPZ mutations associated with CMT1B.

METHODS

The two families were evaluated clinically, electrophysiologically, and genetically. The wild-type and mutant P(0) fused with fluorescent proteins were expressed in vitro to monitor their intracellular trafficking. Adhesion assay was also performed to evaluate the adhesiveness of cells.

RESULTS

The 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 13.6m/s, respectively. Fluorescence analysis demonstrated that the P(0) I135M protein was located on the cell membrane, but the P(0) Q187PfsX63 protein was retained ectopically in the endoplasmic reticulum and Golgi apparatus. Adhesion assay demonstrated a defective adhesiveness of cells expressing either mutant P(0) protein, and P(0) Q187PfsX63 had a more prominent defect of self-adhesive ability than P(0) I135M.

CONCLUSIONS

This 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.