CMT 1B: MPZ mutation G123S characterization - Evidence for a complex pathogenesi

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NEUROLOGY 2008;70:273-277

MPZ mutation G123S characterization - Evidence for a complex

pathogenesis in CMT disease

Y. C. Lee, MD, C.T.R. Yu, PhD, K. P. Lin, MD, M. H. Chang, MD, S. L.

Hsu, PhD, Y. F. Liu, MSc, Y. C. Lu, BS and B. W. Soong, MD, PhD

From the Section of Neurology (Y.C.L., M.H.C., Y.F.L.) and

Department of Education and Research (S.L.H.), Taichung Veterans

General Hospital, Taichung, Taiwan; Department of Neurology (Y.C.L.,

K.P.L., M.H.C., B.W.S.) and Institute of Clinical Medicine (Y.C.L.),

National Yang-Ming University School of Medicine, Taipei, Taiwan;

Graduate Institute of Biomedicine and Biomedical Technology

(C.T.R.Y., S.L.H.), National Chi Nan University, Nantou, Taiwan; and

The Neurological Institute (K.P.L., Y.C.L., B.W.S.), Taipei Veterans

General Hospital, Taipei, Taiwan.

Objectives: To characterize the clinical and cellular phenotypes of

a novel MPZ mutation identified in a Chinese family with Charcot–

Marie–Tooth (CMT) disease type 1B.

Methods: The family was evaluated clinically,

electrophysiologically, pathologically, and genetically. The wild-

type and mutant P0 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 novel MPZ mutation, c.367G>A, is associated with a late-

onset demyelinating CMT phenotype with autosomal dominant

inheritance. The median motor nerve conduction velocities of

patients in this family ranged from 15.7 to 19.6 m/second. The

neuropathologic studies from a sural nerve biopsy revealed a severe

loss of myelinated fibers, and some onion bulb formation with

clusters of regenerative fibers. Fluorescence analysis demonstrated

that the mutant protein was retained ectopically in the endoplasmic

reticulum and Golgi apparatus. Adhesion assay demonstrated a

defective adhesiveness of cells expressing the mutant P0G123S

protein.

Conclusion: The novel P0G123S mutation is associated with typical

findings of late-onset demyelinating polyneuropathy in the

electrophysiologic and pathologic studies, putatively resulting from

aberrant intracellular trafficking of the mutant P0 protein, which

compromises the adhesiveness of the cells.

Abbreviations: AI = aggregation index; cDNA = complementary DNA; CMT

= Charcot–Marie–Tooth; DAPI = 4'-6-diamidino-2-phenylindole; ER =

endoplasmic reticulum; NCV = nerve conduction velocity.