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NEUROLOGY 2006;67:1141-1146
© 2006 American Academy of Neurology

Skin biopsies demonstrate MPZ splicing abnormalities in Charcot-Marie-Tooth neuropathy 1B

A. Sabet, MD, J. Li, MD, PhD, K. Ghandour, BA, Q. Pu, MD, PhD, X. Wu, MD, PhD, J. Kamholz, MD, PhD, M. E. Shy, MD and F. Cambi, MD, PhD

From the Department of Neurology (A.S., F.C.), University of Kentucky, Lexington; and Department of Neurology (J.L., K.G., Q.P., X.W., J.K., M.E.S.) and Center for Molecular Medicine and Genetics (K.G., Q.P., X.W., J.K., M.E.S.), Wayne State University, Detroit, MI.

Address correspondence and reprint requests to Dr. Franca Cambi, University of Kentucky, Department of Neurology, KY Clinic L445, Lexington, KY 40536; e-mail: franca.cambi{at}uky.edu

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.

Editorial, see page 1114

Supported in part by grants from the National Institute of Neurologic Disorders and Stroke (RO1NS041319-05) and MDA (MDA4029).

Disclosure: The authors report no conflicts of interest.

Received March 29, 2006. Accepted in final form June 15, 2006.


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