title: Altered trafficking and adhesion function of MPZ mutations and phenotypes of Charcot-Marie-Tooth disease 1B.
abstract: We previously reported familial cases characterized by Charcot-Marie-Tooth disease (CMT) phenotype with abnormal myelin foldings and MPZ Ile62Phe mutation. To further clarify the molecular mechanisms in this family, we produced wild-type MPZ, Ile62Phe mutant and other mutations in the neighboring regions producing thin myelin sheaths (Ser63del, Ser63Cys and Ser63Phe) by site-specific mutagenesis and transfected these into rat pheochromocytoma cells (PC12). We investigated the expression and aggregation properties of the MPZ protein through immunoblotting, immunohistochemical staining and adhesion assay. MPZ protein with Ile62Phe mutation was immunohistochemically detectable mainly in the plasma membrane of the cells, and it induced a cell aggregation behavior different from the other mutations or the wild-type MPZ. These studies suggested that MPZ Ile62Phe mutation in CMT1B with abnormal myelin folding induced dysregulation of adhesion function of the MPZ protein in a manner unlike those seen in cells with other mutations. The present study provides evidence that the site and nature of amino acid substitutions in the MPZ protein are closely related to the abnormal myelination in CMT1B.
authors.affiliation: Third Department of Internal Medicine, Kagoshima University Faculty of Medicine, Sakuragaoka 8-35-1, Kagoshima City 890-8520, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Matsuyama
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takashima
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Osame
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D002648:Child; D004247:DNA / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007532:Isoleucine / Q000235:genetics; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D018993:Myelin P0 Protein / Q000032:analysis* / Q000235:genetics*; D016716:PC12 Cells; D010641:Phenotype; D010649:Phenylalanine / Q000235:genetics; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000235:genetics*; D051381:Rats; D014162:Transfection
chemical_list: D018993:Myelin P0 Protein; D007532:Isoleucine; D010649:Phenylalanine; D004247:DNA