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MPZ mutation G123S characterization

Evidence for a complex pathogenesis in CMT disease

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.

Address correspondence and reprint requests to Dr. Bing-Wen Soong, The Neurological Institute, Taipei Veterans General Hospital, #201, Sec. 2, Shih-Pai Road, Peitou District, Taipei, Taiwan 11217, Republic of China bwsoong{at}vghtpe.gov.tw

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.

Supported by grants (TCVGH-953404C and TCVGH-963404C) from Taichung Veterans General Hospital; grants (VGH-94-297 and V95CI-113) from Taipei Veterans General Hospital; grants (DOH95-HP-2209) from the Bureau of Health Promotion, Department of Health, Taiwan, Republic of China; and grants (NSC94-2321-B-010-008 and NSC95-2321-B-010-003) from the National Science Council, Taiwan, Republic of China.

Disclosure: The authors report no conflicts of interest.

Received February 21, 2007. Accepted in final form July 2, 2007.