Clinical and cellular characterization of two novel MPZ mutations, p.I135M and p.Q187PfsX63.
OBJECTIVE
We report the clinical and cellular phenotypes of two novel MPZ mutations associated with CMT1B.


METHODS
The two families were evaluated clinically, electrophysiologically, and genetically. The wild-type and mutant P(0) 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 two novel heterozygous MPZ mutations, p.I135M and p.Q187PfsX63, are associated with a childhood-onset demyelinating polyneuropathy. The median motor nerve conduction velocities of the two index patients carrying each mutation were 12.9 and 13.6m/s, respectively. Fluorescence analysis demonstrated that the P(0) I135M protein was located on the cell membrane, but the P(0) Q187PfsX63 protein was retained ectopically in the endoplasmic reticulum and Golgi apparatus. Adhesion assay demonstrated a defective adhesiveness of cells expressing either mutant P(0) protein, and P(0) Q187PfsX63 had a more prominent defect of self-adhesive ability than P(0) I135M.


CONCLUSIONS
This study expanded the spectrum of the MPZ mutations and revealed two disparate mechanisms of MPZ mutations associated with a typical CMT1B phenotype. Other modifying genetic, epigenetic, or environmental factors on CMT1B may exist to explain the discrepancy between the cellular phenotypes.
Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Kon-Ping
KP
Lin
Bing-Wen
BW
Soong
Ming-Hong
MH
Chang
Wei-Ta
WT
Chen
Jer-Li
JL
Lin
Wei-Ju
WJ
Lee
Yi-Chung
YC
Lee
D000328:Adult; D000818:Animals; D001284:Atrophy / Q000209:etiology; D016466:CHO Cells; D002448:Cell Adhesion / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000235:genetics; D003711:Demyelinating Diseases / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008856:Microscopy, Fluorescence; D018908:Muscle Weakness / Q000209:etiology; D009154:Mutation / Q000502:physiology*; D018993:Myelin P0 Protein / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D009493:Neurosurgery; D010375:Pedigree; D011115:Polyneuropathies / Q000235:genetics / Q000473:pathology; D014162:Transfection
C560547:MPZ protein, human; D018993:Myelin P0 Protein; D004247:DNA