Skin biopsies demonstrate MPZ splicing abnormalities in Charcot-Marie-Tooth neuropathy 1B.
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.
Sabet
A
A
Department of Neurology, University of Kentucky, Lexington, KY 40536, USA.
Li
J
J
Ghandour
K
K
Pu
Q
Q
Wu
X
X
Kamholz
J
J
Shy
M E
ME
Cambi
F
F
D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018993:Myelin P0 Protein / Q000235:genetics*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism*; D010375:Pedigree; D012867:Skin / Q000294:innervation* / Q000378:metabolism* / Q000473:pathology
D018993:Myelin P0 Protein