title: Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration.
abstract: Mutations in the major peripheral nervous system (PNS) myelin protein, myelin protein zero (MPZ), cause Charcot-Marie-Tooth Disease type 1B (CMT1B), typically thought of as a demyelinating peripheral neuropathy. Certain MPZ mutations, however, cause adult onset neuropathy with minimal demyelination but pronounced axonal degeneration. Mechanism(s) for this phenotype are unknown. We performed an autopsy of a 73-year-old woman with a late-onset neuropathy caused by an H10P MPZ mutation whose nerve conduction studies suggested severe axonal loss but no demyelination. The autopsy demonstrated axonal loss and reorganization of the molecular architecture of the axolemma. Segmental demyelination was negligible. In addition, we identified focal nerve enlargements containing MPZ and ubiquitin either in the inner myelin intralaminar and/or periaxonal space that separates axons from myelinating Schwann cells. Taken together, these data confirmed that a mutation in MPZ can cause axonal neuropathy, in the absence of segmental demyelination, thus uncoupling the two pathological processes. More important, it also provided potential molecular mechanisms as to how the axonal degeneration occurred: either by disruption of glial-axon interaction by protein aggregates or by alterations in the molecular architecture of internodes and paranodes. This report represents the first study in which the molecular basis of axonal degeneration in the late-onset CMT1B has been explored in human tissue.
authors.affiliation: Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. junli@med.wayne.edu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Bai
authors.forename: Emilia
authors.initials: E
authors.lastname: Ianakova
authors.forename: Marina
authors.initials: M
authors.lastname: Grandis
authors.forename: Fred
authors.initials: F
authors.lastname: Uchwat
authors.forename: Anna
authors.initials: A
authors.lastname: Trostinskaia
authors.forename: Karen M
authors.initials: KM
authors.lastname: Krajewski
authors.forename: James
authors.initials: J
authors.lastname: Garbern
authors.forename: William J
authors.initials: WJ
authors.lastname: Kupsky
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001344:Autopsy; D015415:Biomarkers / Q000378:metabolism; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D009154:Mutation; D018993:Myelin P0 Protein / Q000235:genetics* / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012183:Retrograde Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D015415:Biomarkers; D018993:Myelin P0 Protein