Objective: To demonstrate that intronic mutations in the myelin protein zero (MPZ) cause Charcot-Marie-Tooth neuropathy 1B (CMT1B) by disrupting MPZ splicing.
Methods: We report a family with a T>G transversion at the invariant + 2 position in intron 4 of MPZ (c.614 + 2T>G) that abolishes 5' donor site recognition and is predicted to alter MPZ splicing. We obtained detailed clinical and neurophysiologic analysis of the family. We performed skin biopsies to investigate splicing abnormalities, MPZ protein levels, and localization in myelinated nerves.
Results: Patients developed a late onset neuropathy with minimally slow nerve conduction velocities. Skin biopsies confirmed the predicted skipping of exon 4 and downstream frameshift of the mutant MPZ. Quantitative immuno-EM demonstrated normal nerve MPZ levels, suggesting that the mutant MPZ was transported to compact myelin.
Conclusions: Intronic mutations cause CMT1B by disrupting splicing and certain MPZ mutations may cause neuropathy by interacting with the wild type MPZ in the extracellular space of compact myelin.