Type 1B: Skin biopsies demonstrate MPZ splicing abnormalities in CMT

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Neurology. 2006 Oct 10;67(7):1141-6.

Skin biopsies demonstrate MPZ splicing abnormalities in Charcot-

Marie-Tooth neuropathy 1B.

Sabet A, Li J, Ghandour K, Pu Q, Wu X, Kamholz J, Shy ME, Cambi F.

Department of Neurology, University of Kentucky, Lexington, KY

40536, USA.

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.